Bi-aryl meta-pyrimidine inhibitors of kinases

ABSTRACT

The invention provides biaryl meta-pyrimidine compounds having the general structure (A). The pyrimidine compounds of the invention are capable of inhibiting kinases, such as members of the Jak kinase family, and various other specific receptor and non-receptor kinases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part application of U.S. patentapplication Ser. No. 11/588,638 filed Oct. 26, 2006, which claims thebenefit of priority under 35 U.S.C. § 119(e) of U.S. patent applicationsSer. Nos. 60/732,629 filed Nov. 1, 2005, and 60/838,003 filed Aug. 15,2006, the entire content of which is incorporated herein by reference.

FIELD OF INVENTION

The present invention relates to the field of inhibitors of proteintyrosine kinases, their pharmaceutically acceptable compositionscomprising the compounds of the invention and the methods of using thecompositions in the treatment of various disorders. In particular, thepresent invention relates to inhibitors of the JAK family of proteintyrosine kinases.

BACKGROUND OF INVENTION

Protein kinases are families of enzymes that catalyze thephosphorylation of specific residues in proteins, broadly classifiedinto tyrosine and serine/threonine kinases. Inappropriate kinaseactivity, arising from mutation, over-expression, or inappropriateregulation, dys-regulation or de-regulation, as well as over- orunder-production of growth factors or cytokines has been implicated inmany diseases, including but not limited too cancer, cardiovasculardiseases, allergies, asthma and other respiratory diseases, autoimmunediseases, inflammatory diseases, bone diseases, metabolic disorders, andneurological and neurodegenerative disorders such as Alzheimer'sdisease. Inappropriate kinase activity triggers a variety of biologicalcellular responses relating to cell growth, cell differentiation,survival, apoptosis, mitogenesis, cell cycle control, and cell mobilityimplicated in the aforementioned and related diseases.

Protein kinases have emerged as an important class of enzymes as targetsfor therapeutic intervention. In particular, the JAK family of cellularprotein tyrosine kinases (Jak1, Jak2, Jak3, and Tyk2) play a centralrole in cytokine signaling (Kisseleva et al, Gene, 2002, 285, 1; Yamaokaet al. Genome Biology 2004, 5, 253)). Upon binding to their receptors,cytokines activate JAK which then phosphorylate the cytokine receptor,thereby creating docking sites for signaling molecules, notably, membersof the signal transducer and activator of transcription (STAT) familythat ultimately lead to gene expression. Numerous cytokines are known toactivate the JAK family. These cytokines include, the IFN family(IFN-αs/β/ω/Limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), the gp130family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, CT-1, Leptin,IL-12, IL-23), γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4,IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH,PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), andG-protein coupled receptors (AT1).

Until recently, the therapeutic potential of JAK inhibitors has focusedon diseases affecting various pathologies of the immune system. Theseinclude, but are not limited to atopy (allergic asthma, atopicdermatitis, allergic rhinitis), cell mediated hypersensitivity (allergiccontact dermatitis, hypersensitivity pneumonitis), rheumatic diseases(systemic lupus erythematosus (SLE), rheumatoid arthritis, juvenilearthritis, Sjogren's Syndrome, scleroderma, polymyositis, ankylosingspondylitis, psoriatic arthritis), transplantation (transplantrejection, graft vs host disease), viral diseases (Epstein Barr Virus,Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, HumanPapilloma Virus), cancer (leukemia, lymphoma), cardiovascular disease(cardiac hypertrophy, atherosclerosis and arteriosclerosis),neurodegenerative diseases (motor neuron disease), food allergy,inflammatory bowel disease, Crohn's disease, cutaneous inflammation, andimmune suppression induced by solid tumors. Most efforts to date havetargeted JAK3 inhibition for immunosuppression, for example organtransplantation and allograft acceptance (for a review, see Borie et al.Current Opinion in Investigational Drugs, 2003, 4(11), 1297).

Most recently, two significant findings of the role of the EPO-JAK2signaling pathway in myeloproliferative disorders and prolfierativediabetic retinopathy were found. First, a gain-of-function, somatic(acquired) mutation of the JAK2 kinase (V617F) was reported to be acausative factor in a number of “typical” myeloproliferative disorders,including polycethemia vera, essential thrombocythemia and melofibrosiswith myeloid metaplasia, and the mutation has been found in patientswith either “atypical” myeloproliferative disorders and myelodysplasticsyndrome (for reviews see Tefferi and Gilliland, Cell Cycle 2005, 4(8),e61; Pesu et. al. Molecular Interventions 2005, 5(4), 211). Additionallyit was found that (a) the V617F JAK2 mutation was associated withconstitutive phosphorylation of JAK2 and its downstream effectors aswell as induction of erythropoietin hypersensitivity in cell basedexperiments, (b) V617F JAK2-indcued cell proliferation signals wereinhibited by small molecule inhibitors of JAK2, and (c) murine bonemarrow transduced with a retrovirus containing V617F JAK2 incudederythrocytosis in the transplanted mice.

Furthermore, recently it has been found that mutations in EPO-R alsokeep the JAK pathway constitutively activated leading tomyleoproliferative disorders.

Second, EPO was found to be a potent angiogenic factor in proliferativediabetic retinopathy, a major cause of vision loss affecting diabetic,working-age persons (see for example Aiello, New England Journal ofMedicine, 2005, 353 (8), 839; Watanabe et al. New England Journal ofMedicine 2005 353 (8), 782).

Further, findings from the Watanabe research showed (a) intraocular EPOlevels and VEGF (another well-known angiogenic factor in proliferativediabetic retinopathy) were significantly higher among those withproliferative diabetic retinopathy than those with quiescent disease ornon-diabetic control, (b) EPO and VEGF levels were not closelycorrelated, (c) EPO levels were more strongly correlated with thepresence of proliferative diabetic retinopathy than VEGF, (d) EPOstimulated growth and intracellular signaling in retinal endothelialcells, and (e) inhibitors of either EPO or VEGF reduced hypoxia-inducedretinal neovascularization in rodent models.

Recently it has been shown that mutations in the EPO receptor may alsoaffect the signaling related to the JAK pathway and this may haveimplications in terms of disease states where JAK signaling is importantin the cell cycle.

There is another feature regarding inhibitors of the JAK pathway. It hasbeen demonstrated that the JAK pathway may be recruited in cell survivaland proliferation. For example, in the case of the cells that arePhiladelphia chromosome positive that result in chronic myelogenousleukemia (CML), there is evidence that the Jak pathway is recruited inconstitutive activation. Accordingly, using a JAK inhibitor may have usein CML in which the Philadephia chromosome has been shown to produce thehybrid Bcr-Abl, thus keeping cells constitutively active.

More telling is that in cases of resistance mutations that arise onaccount of specific inhibitors to BCR-ABL, as in the case of the T315Igatekeeper mutation, or any other mutation, it may be possible to use aJAK inhibitor on account of the pathway used by the BCR-ABL mutant (asin the case of BCR-ABL(T315I) mutation) utilizing the Jak pathway. ThusJak inhibitors may be used in the treatment of patients with resistanceto known therapies where BCR-ABL is directly targeted and drugresistance has now been shown as the dominant (50-90%) of all resistancein patients where existing therapies fail.

The use of JAK inhibitors may also find utility in other myeloid diseasestates, both blood disorders and other disease states with myeloidimplications, and other disease states in which the JAK pathway isimplicated directly or indirectly.

Accordingly, there is a need to develop compounds useful as inhibitorsof kinases, particularly, JAK kinase, given the inadequate treatmentsavailable for the aforementioned diseases where the JAK signalingpathway is dysregulated, or recruited directly or indirectly.

SUMMARY

According to one embodiment, a compound having the structure (A) isprovided:

According to another embodiment, a method is provided for treating anangiogenic-associated disorder, the method including administering to asubject in need thereof a therapeutically effective amount of at leastone compound having the structure (A), or pharmaceutically acceptablesalts, hydrates, solvates, polymorphs, crystal forms, N-oxides, andindividual enatiomers and diastereomers thereof, to a subject in need ofsuch treatment.

According to other embodiments, pharmaceutical compositions and articlesof manufacture are provided, including at least one compound having thestructure (A), or pharmaceutically acceptable salts, hydrates, solvates,crystal forms and individual diastereomers thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic illustration of JAK2 signaling pathway.

FIG. 2 is an illustration of co-crystallization of a compound of thepresent invention with JAK2 kinase.

FIG. 3 shows that JAK2^(V617F) mutation is present in a large number ofpatients with an unmet clinical need.

FIG. 4 illustrates schematically inhibition of JAK2^(V617F) kinase by acompound of the present invention.

FIG. 5 illustrates schematically selectively reduction of erythrocytecolony formation in human stem cells by a compound of the presentinvention.

FIG. 6 shows selective reversal of engraftment of human stem cellsexpressing JAK2^(V617F) using compound of the present invention.

FIG. 7 illustrates schematically that an orally administered compound ofthe present invention inhibits JAK2^(V617F) signaling in vivo.

FIG. 8 shows reversal of polycythemia vera-like symptoms in mice by oraladministration of a compound of the present invention.

FIG. 9 shows 1YVJ crystal structure of the JAK3 kinase domain in complexwith a staurosporine analog.

FIG. 10 shows design-template regions analyzed in designing inhibitorstargeting JAK2.

FIG. 11 shows the structure of a compound used in homology model ofJAK2.

FIG. 12 illustrates homology between JAK2 and JAK3 at the ATP bindingsite.

FIG. 13 shows that small molecule JAK2 inhibitor development is enabledby location of V617F mutation distal from ATP binding pocket.

FIG. 14 provides an illustration of the use of molecular modeling toenable rational design of a large number of potent small moleculeinhibitors of JAK2.

FIG. 15 demonstrates the differences between JAK2 and JAK3selection—There are few amino acid differences around the ATP bindingsite that can be exploited for selectivity.

FIG. 16 provides another illustration of the use of molecular modelingto enable rational design of a large number of potent small moleculeinhibitors of JAK2.

FIG. 17 provides an illustration of high selectiveness of a compound ofthe present invention as an inhibitor for variety of kinases.

FIG. 18 demonstrates selectively inhibition of JAK2-mediated cellproliferation by a compound of the present invention.

FIG. 19 demonstrates that a compound of the present invention reducesJAK2-induced STAT5 phosphorylation.

FIG. 20 demonstartes allometric scaling of pharmacokinetic parametersfor one compound of the present invention.

FIG. 21 demonstrates that certain compounds of the present inventionincrease survival and reduce JAK2^(V617F) cell burden after oral dosingin rodent model.

FIG. 22 demonstrates inhibition of JAK2(V617F)-driven cell proliferationby JAK2 inhibitors.

FIG. 23 demonstrates inhibition JAK2(V617F)-mediated proteinphosphorylation and inducing apoptosis in JAK(V617F) cells by a compoundof the invention.

FIG. 24 demonstrates survival benefit of a compound of the invention inJAK2(V617F)-driven circulating tumor model.

FIG. 25 demonstrates that a compound of the invention reducesJAK2(V617F) cell burden in JAK2(V617F)-driven circulating tumor model.

FIG. 26 demonstrates enhanced erythroid differentiation of normalprogenitors transduced with lentiviral JAK2 V617F.

FIG. 27 shows inhibition of Jak2 induced erythroid differentiation by acompound of the present invention.

FIG. 28 shows alteration of erythroid skewed differentiation inPolycythemia Vera (PV) with a specific JAK2 inhibitor.

FIG. 29 shows that PV HSC have enhanced erythroid engraftment potential.

FIG. 30 shows that JAK2 overexpression enhances human engraftment inRAG2−/−γc−/− mice at 8 weeks post-transplant.

FIG. 31 shows a compound of the present invention and its selectivenessas a JAK2 inhibitor in vitro.

FIG. 32 shows inhibition of JAK2 in vitro by a compound of the presentinvention.

FIG. 33 shows selectively inducement of apoptosis ofJAK2V617F-expressing cells by a compound of the present invention.

FIG. 34 shows selectively inducement of cell cycle arrest ofJAK2V617F-expressing cells by a compound of the present invention.

FIG. 35 shows inhibition of phosphorylation of JAK2V617F, STAT5, andSTAT3 in JAK2V617F-expressing cells by a compound of the presentinvention.

FIG. 36 shows treatment OF JAK2V617F-induced hematopoietic malignancy inmice by a compound of the present invention.

FIG. 37 shows inhibition of hematopoietic colony formation in vitro by acompound of the present invention.

DETAILED DESCRIPTION A. TERMS AND DEFINITIONS

The following terminology and definitions apply as used in the presentapplication, generally in conformity with the terminology recommended bythe International Union of Pure and Applied Chemistry (IUPAC):

The term “heteroatom” refers to any atom other than carbon, for example,N, O, or S.

The term “aromatic” refers to a cyclically conjugated molecular entitywith a stability, due to delocalization, significantly greater than thatof a hypothetical localized structure, such as the Kekulé structure.

The term “heterocyclic,” when used to describe an aromatic ring, refersto the aromatic rings containing at least one heteroatom, as definedabove.

The term “heterocyclic,” when not used to describe an aromatic ring,refers to cyclic (i.e., ring-containing) groups other than aromaticgroups, the cyclic group being formed by between 3 and about 14 carbonatoms and at least one heteroatom described above.

The term “substituted heterocyclic” refers, for both aromatic andnon-aromatic structures, to heterocyclic groups further bearing one ormore substituents described below.

The term “alkyl” refers to a monovalent straight or branched chainhydrocarbon group having from one to about 12 carbon atoms, for example,methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl,n-pentyl (also known as n-amyl), n-hexyl, and the like. The term “loweralkyl” refers to alkyl groups having from 1 to about 6 carbon atoms.

The term “substituted alkyl” refers to alkyl groups further bearing oneor more substituents such as hydroxy, alkoxy, mercapto, cycloalkyl,substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl,substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, halogen, cyano, nitro, amino, amido, aldehyde,acyl, oxyacyl, carboxyl, sulfonyl, sulfonamide, sulfuryl, and the like.

The term “alkenyl” refers to straight-chained or branched hydrocarbylgroups having at least one carbon-carbon double bond, and having betweenabout 2 and about 12 carbon atoms, and the term “substituted alkenyl”refers to alkenyl groups further bearing one or more substituentsdescribed above.

The term “alkynyl” refers to straight-chained or branched hydrocarbylgroups having at least one carbon-carbon triple bond, and having betweenabout 2 and about 12 carbon atoms, and the term “substituted alkynyl”refers to alkynyl groups further bearing one or more substituentsdescribed above.

The term “aryl” refers to aromatic groups having between about 5 andabout 14 carbon atoms and the term “substituted aryl” refers to arylgroups further bearing one or more substituents described above.

The term “heteroaryl” refers to aromatic rings, where the ring structureis formed by between 3 and about 14 carbon atoms and by at least oneheteroatom described above, and the term “substituted heteroaryl” refersto heteroaryl groups further bearing one or more substituents describedabove.

The term “alkoxy” refers to the moiety alkyl, wherein alkyl is asdefined above, and the term “substituted alkoxy” refers to alkoxy groupsfurther bearing one or more substituents described above.

The term “cycloalkyl” refers to alkyl groups having between 3 and about8 carbon atoms arranged as a ring, and the term “substituted cycloalkyl”refers to cycloalkyl groups further bearing one or more substituentsdescribed above.

The term “alkylaryl” refers to alkyl-substituted aryl groups and theterm “substituted alkylaryl” refers to alkylaryl groups further bearingone or more substituents described above.

The term “arylalkyl” refers to aryl-substituted alkyl groups and theterm “substituted arylalkyl” refers to arylalkyl groups further bearingone or more substituents described above.

The term “arylalkenyl” refers to aryl-substituted alkenyl groups and theterm “substituted arylalkenyl” refers to arylalkenyl groups furtherbearing one or more substituents described above.

The term “arylalkynyl” refers to aryl-substituted alkynyl groups and theterm “substituted arylalkynyl” refers to arylalkynyl groups furtherbearing one or more substituents described above.

The term “arylene” refers to divalent aromatic groups having between 5and about 14 carbon atoms and the term “substituted arylene” refers toarylene groups further bearing one or more substituents described above.

The term “chemically connected” is defined as forming a chemical entityin which two moieties form a direct chemical bond between them.

The term “kinase” refers to any enzyme that catalyzes the addition ofphosphate groups to a protein residue; for example, serine and threoninekinases catalyze the addition of phosphate groups to serine andthreonine residues.

The term “JAK kinase” refers to an enzyme found in cells in the immunesystem that participates in the cell signaling process resulting in thedevelopment of white blood cells.

The term “therapeutically effective amount” refers to the amount of thecompound or pharmaceutical composition that will elicit the biologicalor medical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, e.g., restoration or maintenance of vasculostasis orprevention of the compromise or loss or vasculostasis; reduction oftumor burden; reduction of morbidity and/or mortality.

The term “pharmaceutically acceptable” refers to the fact that thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The terms “administration of a compound” or “administering a compound”refer to the act of providing a compound of the invention orpharmaceutical composition to the subject in need of treatment.

The term “antibody” refers to intact molecules of polyclonal ormonoclonal antibodies, as well as fragments thereof, such as Fab andF(ab′)₂, Fv and SCA fragments which are capable of binding an epitopicdeterminant.

The term “vasculostasis” refers to the maintenance of the homeostaticvascular functioning leading to the normal physiologic functioning.

The term “vasculostatic agents” refers to agents that seek to addressconditions in which vasculostasis is compromised by preventing the lossof or restoring or maintaining vasculostasis.

B. EMBODIMENTS OF THE INVENTION

According to an embodiment of the invention, compounds having thestructure (A) are provided for treatment of various diseases, disorders,and pathologies:

In the structure (A), X can be any of a bond, O, C═O, SO₂, or CH₂ and Ycan be a bond or NR⁹; or X and Y taken together can be a bond. Further,in the structure (A) each of R¹ and R² can be any of H, C₁-C₆substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; or R¹and R² taken together can be a bond; or R¹ and R² taken together canform a moiety such as one of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m),(CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), or (CH₂)_(r)—O—(CH₂)_(m), wherein each of p, q,r, n, m is idependently an integer having the value between 0 and 6.

Further, in the structure (A) R⁹ can be one of H, C₁-C₆ alkyl, C₁-C₆cycloalkyl, C₁-C₆ branched alkyl, C₁-C₆ substituted alkyl, C₁-C₆aminoalkyl, or C₁-C₆ hydroxyalkyl; G₀ can be one of N, O, H, of CH, withthe proviso that if G₀ is N, then each of R³ and R⁴ can be one of H,C₁-C₆ alkyl, C₁-C₆ substituted or unsubstituted hydroxyalkyl oraminoalkyl, C₁-C₆ substituted or unsubstituted branched alkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, or R³ and R⁴ taken together can form a moiety such as one of(CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), or(CH₂)_(r)—O—(CH₂)_(m).

There are some additional provisos further directed to G₀ in thestructure (A). More specifically, if G₀ is N, then R¹ and R⁹ takentogether can form a moiety such as one of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), or (CH₂)_(r)—O—(CH₂)m; or R¹ and R⁴ takentogether can form a moiety such as one of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), or (CH₂)_(r)—O—(CH₂)m; or R⁹ and R⁴ takentogether can form a moiety such as one of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), or (CH₂)_(r)—O—(CH₂)_(m); or R³ and R⁴ takentogether can form a moiety such as one of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁶—(CH₂)_(m), or (CH₂)_(r)—O—(CH₂)_(m).

If in the structure (A) G₀ is O, then R³ can be one of H, C₁-C₆ alkyland C₁-C₆ substituted or unsubstituted hydroxyalkyl or aminoalkyl,substituted or unsubstituted branched alkyl, substituted orunsubstituted cycloalkyl, substituted heterocyclic connected throughcarbon or nitrogen, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl connected through carbon or nitrogen, with nogroup R⁴; R¹ and R⁹ taken together can form a moiety such as one of(CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), or(CH₂)_(r)—O—(CH₂)_(m); or R¹ and R³ taken together can form a moietysuch as one of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), or(CH₂)_(r)—O—(CH₂)_(m); or R⁹ and R³ taken together can form a moietysuch as one of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), or(CH₂)_(r)—O—(CH₂)_(m).

If in the structure (A) G₀=CH, then each of R³ and R⁴ can be one of H,C₁-C₆ alkyl, C₁-C₆ substituted or unsubstituted hydroxyalkyl oraminoalkyl, C₁-C₆ substituted or unsubstituted branched alkyl,substituted or unsubstituted aryl, C₁-C₆ substituted or unsubstitutedheterocycle connected through carbon or nitrogen, or substituted orunsubstituted heteroaryl connected through carbon or nitrogen, or R³ andR⁴ taken together can form a moiety such as one of(CHR⁹)_(r)—(CHR⁹)_(m)—(CHR⁹)_(p), (CHR⁹)_(r)—S—(CHR⁹)_(m),(CHR⁹)_(r)—SO—(CHR⁹)_(m), (CHR⁹)_(r)—SO₂—(CHR⁹)_(m),(CHR⁹)_(r)—NR⁹—(CHR⁹)_(m), or (CHR⁹)_(r)—O—(CHR⁹)_(m).

Further, in the structure (A) G can be N or CR⁶, and each G isindependent of each other G, with the further proviso that not more thantwo groups G can be N, with the further proviso that for each CR⁶, eachR⁶ is independent of each other group R⁶.

Further, in the structure (A) R⁵ is methyl and the moiety Q is as shownbelow

In the moiety Q, each of R⁶, R⁷, R⁸ can be one of H, C₁-C₆ substitutedor unsubstituted alkyl, C₁-C₆ substituted or unsubstituted alkenyl,C₁-C₆ substituted or unsubstituted alkynyl, C₁-C₆ substituted orunsubstituted hydroxyalkyl or aminoalkyl, C₁-C₆ substituted orunsubstituted branched alkyl, C₁-C₆ substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl connected through carbonor a heteroatom, substituted or unsubstituted heteroaryl connectedthrough carbon or a heteroatom, C₁-C₆ alkoxy, a halogen, CF₃, —OCF₃,CHR³R⁴, SR³, SOR³, SO₂R³, SO₂NR³R⁴, SO₃R³, POR³, PO₂R³, PO₂NR³R⁴,PO₂CR³R⁴, PO₃R³, NR³R⁴, NO₂, CN, OH, CONR³R⁴, COR³, COOR³, NR³COR⁴,NR³CONR³R⁴, OCONR³R⁴, CSNR³R⁴, CSR³, NR³CSNR³R⁴, SCONR³R⁴, SCSNR³R⁴, orSCSNR³R⁴; or any of R⁶ and R⁷ taken together, or R⁷ and R⁸ takentogether, or R⁶ and R⁸ taken together can form a moiety independentlyselected from any of —HN—CH═CH—, —HN—N═CH—, —HN—N═N—, —O(CH₂)_(n)O—,—S(CH₂)_(n)S—, —N═CH—S—, —CH═N—O—, —CH═N—S—, —N═CH—O—, —C═N—O—, —C═N—O—,—CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —O—CH═CH, and —S—CH═CH—; orR³ and R⁴ taken together can form a moiety such as one of(CHR⁹)_(r)—(CHR⁹)_(m)—(CHR⁹)_(p), (CHR⁹)_(r)—S—(CHR⁹)_(m),(CHR⁹)_(r)—SO—(CHR⁹)_(m), (CHR⁹)_(r)—SO₂—(CHR⁹)_(m),(CHR⁹)_(r)—NR⁹—(CHR⁹)_(m), or (CHR⁹)_(r)—O—(CHR⁹)_(m).

Further, in the structure (A), A can be one of O, NR³, CR³R⁴, S, SO, andSO₂; and in the moiety Q, G₁ can be any of CH, N, NH, S, and O, and G₂can be any of CR⁷, N, NH, S, and O, with each group R⁷ being independentof every other group R⁷; and if G₁ or G₂ is NH, S, or O, then Q is afive membered heteroaromatic ring, optionally fused to a six memberaromatic or non-aromatic ring; and if G₁ or G₂ is N, then Q is a five ora six membered aromatic ring, optionally fused to a six member aromaticor non-aromatic ring, with the further proviso that X or G₀ includes atleast one heteroatom included with X and selected from O, S and N, or G₀comprises at least four non-hydrogen atoms, inclusive of the heteroatom,and R³ and R⁴, or R¹ and R⁹, or R¹ and R⁴, or R⁹ and R⁴ taken togethercan form an aromatic, heteroaromatic, cyclic or heterocyclic ringsystem, or if a noncyclic system is present, then more than oneheteroatom is present, and if A is NR₃, then any of R₆, R₇ or R₈, or anycombination thereof independently includes at least two non-hydrogensubstituents, or if A is NR₃, then Q forms a fused ring from R₆ to R₇,or from R₇ to R₈.

Some exemplary compounds described by structure (A) that can be usedinclude, but are not limited to, the following compounds I through CLXIIshown below:

According to another embodiment of the invention, compounds having thegeneral structure (Z):B—C  (Z)are provided for treatment of various diseases, disorders, andpathologies.

The general structure (Z) includes two chemically connected moieties Band C. The moiety B in the general structure (Z) includes any moietyselected from the following group:

The moiety C in the structure (Z), above, includes any moiety selectedfrom the following group:

The compounds and methods of the present invention, or pharmaceuticallyacceptable salts, hydrates, solvates, crystal forms and individualdiastereomers thereof, either when administered alone or in combinationwith other agents (e.g., chemotherapeutic agents or protein therapeuticagents described below) are useful in treating a variety of disorders,including, but not limited to, for example, myeloproliferativedisorders, proliferative diabetic retinopathy and otherangiogenic-associated disorders including solid tumors and other typesof cancer, eye disease, inflammation, psoriasis, and a viral infection.The kinds of cancer that can be treated include, but are not limited to,an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer,skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma,leukemia (including acute myelogenous leukemia and chronic myelogenousleukemia), kidney cancer, lung cancer, muscle cancer, bone cancer,bladder cancer or brain cancer.

Some examples of the diseases and disorders that can be treated alsoinclude ocular neovasculariaztion, infantile haemangiomas; organhypoxia, vascular hyperplasia, organ transplant rejection, lupus,multiple sclerosis, rheumatoid arthritis, psoriasis, Type 1 diabetes andcomplications from diabetes, inflammatory disease, acute pancreatitis,chronic pancreatitis, asthma, allergies, adult respiratory distresssyndrome, cardiovascular disease, liver disease, other blood disorders,asthma, rhinitis, atopic, dermatitits, autoimmune thryroid disorders,ulerative colitis, Crohn's disease, metastatic melanoma, Kaposi'ssarcoma, multiple myeloma, conditions associated with cytokines, andother autoimmune diseases including glomerulonephritis, scleroderma,chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmunehemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopy (e.g.,allergic asthma, atopic dermatitis, or allergic rhinitis), chronicactive hepatitis, myasthenia gravis, multiple sclerosis, inflammatorybowel disease, graft vs host disease, neurodegenerative diseasesincluding motor neuron disease, Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, Huntington's disease, cerebralischemia, or neurodegenerative disease caused by traumatic injury,strike, gluatamate neurtoxicity or hypoxia; ischemic/reperfusion injuryin stroke, myocardial ischemica, renal ischemia, heart attacks, cardiachypertrophy, atherosclerosis and arteriosclerosis, organ hyoxia, andplatelet aggregation.

Examples of some additional diseases and disorders that can be treatedalso include cell mediated hypersensitivity (allergic contactdermatitis, hypersensitivity pneumonitis), rheumatic diseases (e.g.,systemic lupus erythematosus (SLE), juvenile arthritis, Sjogren'sSyndrome, scleroderma, polymyositis, ankylosing spondylitis, psoriaticarthritis), viral diseases (Epstein Barr Virus, Hepatitis B, HepatitisC, HIV, HTLV1, Vaicella-Zoster Virus, Human Papilloma Virus), foodallergy, cutaneous inflammation, and immune suppression induced by solidtumors.

Embodiments of the present invention also provide articles ofmanufacture that can include a packaging material and a pharmaceuticalcomposition contained within the packaging material. The packagingmaterial can comprise a label which indicates that the pharmaceuticalcomposition can be used for treatment of one or more disordersidentified above.

The pharmaceutical composition can include a compound according to thepresent invention. In addition to a compound of the present invention,the pharmaceutical may also contain other therapeutic agents, and may beformulated, for example, by employing conventional solid or liquidvehicles or diluents, as well as pharmaceutical additives of a typeappropriate to the mode of desired administration (for example,excipients, binders, preservatives, stabilizers, flavors, etc.)according to techniques known in the art of pharmaceutical formulation.

Thus, in one embodiment, the invention provides a pharmaceuticalcomposition including a therapeutic agent and a compound of theinvention. The compound is present in a concentration effective totreat, for example, cancer or to treat another disease or disorderdescribed above.

The compounds of the invention may be formulated into therapeuticcompositions as natural or salt forms. Pharmaceutically acceptablenon-toxic salts include the base addition salts (formed with freecarboxyl or other anionic groups) which may be derived from inorganicbases such as, for example, sodium, potassium, ammonium, calcium, orferric hydroxides, and such organic bases as isopropylamine,trimethylamine, 2-ethylamino-ethanol, histidine, procaine, and the like.Such salts may also be formed as acid addition salts with any freecationic groups and will generally be formed with inorganic acids suchas, for example, hydrochloric, sulfuric, or phosphoric acids, or organicacids such as acetic, citric, p-toluenesulfonic, methanesulfonic acid,oxalic, tartaric, mandelic, and the like.

Salts of the invention can include amine salts formed by the protonationof an amino group with inorganic acids such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, andthe like. Salts of the invention can also include amine salts formed bythe protonation of an amino group with suitable organic acids, such asp-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like.Additional excipients which are contemplated for use in the practice ofthe present invention are those available to those of ordinary skill inthe art, for example, those found in the United States Pharmacopeia Vol.XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention,Inc., Rockville, Md. (1989), the relevant contents of which isincorporated herein by reference. In addition, polymorphs of theinvention compounds are included in the present invention.

Pharmaceutical compositions of the invention may be administered by anysuitable means, for example, orally, such as in the form of tablets,capsules, granules or powders; sublingually; buccally; parenterally,such as by subcutaneous, intravenous, intramuscular, intrathecal, orintracisternal injection or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasallysuch as by inhalation spray; topically, such as in the form of a creamor ointment; or rectally such as in the form of suppositories; in dosageunit formulations containing non-toxic, pharmaceutically acceptablevehicles or diluents. The present compounds may, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release may be achieved by theuse of suitable pharmaceutical compositions comprising the presentcompounds, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentcompounds may also be administered liposomally.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals including, but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species(e.g., chickens).

The pharmaceutical compositions for the administration of the compoundsof this embodiment, either alone or in combination with othertherapeutic agents, may conveniently be presented in dosage unit formand may be prepared by any of the methods well known in the art ofpharmacy. All methods include bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. The pharmaceutical compositions containing theactive ingredient may be in a form suitable for oral use, for example,as tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated to form osmotic therapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.Also useful as a solubilizer is polyethylene glycol, for example. Theaqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a parenterally-acceptable diluent or solventor cosolvent or complexing agent or dispersing agent or excipient orcombination thereof, for example 1,3-butanediol, polyethylene glycols,polypropylene glycols, ethanol or other alcohols, povidones, variousbrands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate,dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, andexcipients such as inorganic salts (e.g., sodium chloride), bufferingagents (e.g., sodium citrate, sodium phosphate), and sugars (e.g.,saccharose and dextrose). Among the acceptable vehicles and solventsthat may be employed are water, dextrose solutions, Ringer's solutionsand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Depending on the condition being treated, these pharmaceuticalcompositions may be formulated and administered systemically or locally.Techniques for formulation and administration may be found in the latestedition of “Remington's Pharmaceutical Sciences” (Mack Publishing Co,Easton Pa.). Suitable routes may, for example, include oral ortransmucosal administration; as well as parenteral delivery, includingintramuscular, subcutaneous, intramedullary, intrathecal,intraventricular, intravenous, intraperitoneal, or intranasaladministration. For injection, the pharmaceutical compositions of theinvention may be formulated in aqueous solutions, preferably inphysiologically compatible buffers such as Hanks' solution, Ringer'ssolution, or physiologically buffered saline. For tissue or cellularadministration, penetrants appropriate to the particular barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art. Pharmaceutical formulations for parenteraladministration include aqueous solutions of the active compounds inwater-soluble form. Additionally, suspensions of the active compoundsmay be prepared as appropriate oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances thatincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents that increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions.

The compounds of the present invention may also be administered in theform of suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of the present invention are employed.(For purposes of this application, topical application shall includemouthwashes and gargles).

In one embodiment, the invention compounds are administered incombination with an anti-inflammatory agent, antihistamines,chemotherapeutic agent, immunomodulator, therapeutic antibody or aprotein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to asubject in need of such treatment. While not wanting to be limiting,chemotherapeutic agents include antimetabolites, such as methotrexate,DNA cross-linking agents, such as cisplatin/carboplatin; alkylatingagents, such as canbusil; topoisomerase I inhibitors such asdactinomicin; microtubule inhibitors such as taxol (paclitaxol), and thelike. Other chemotherapeutic agents include, for example, a vincaalkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic,antifolate, colchicine, demecoline, etoposide, taxane, anthracyclineantibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin,idarubicin, mithoxanthrone, 4-dimethoxy-daunomycin,11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate,adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine,carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin,melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine,thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, ormechlorethamine. While not wanting to be limiting, therapeuticantibodies include antibodies directed against the HER2 protein, such astrastuzumab; antibodies directed against growth factors or growth factorreceptors, such as bevacizumab, which targets vascular endothelialgrowth factor, and OSI-774, which targets epidermal growth factor;antibodies targeting integrin receptors, such as Vitaxin (also known asMEDI-522), and the like. Classes of anticancer agents suitable for usein compositions and methods of the present invention include, but arenot limited to: 1) alkaloids, including, microtubule inhibitors (e.g.,Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers(e.g., Paclitaxel [Taxol], and Docetaxel, Taxotere, etc.), and chromatinfunction inhibitors, including, topoisomerase inhibitors, such as,epipodophyllotoxins (e.g., Etoposide [VP-16], and Teniposide [VM-26],etc.), and agents that target topoisomerase I (e.g., Camptothecin andIsirinotecan [CPT-11], etc.); 2) covalent DNA-binding agents [alkylatingagents], including, nitrogen mustards (e.g., Mechlorethamine,Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran],etc.), nitrosoureas (e.g., Carmustine, Lomustine, and Semustine, etc.),and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine,Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents[antitumor antibiotics], including, nucleic acid inhibitors (e.g.,Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin[Daunomycin, and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin[Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, suchas, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin(Mithramycin), etc.; 4) antimetabolites, including, antifolates (e.g.,Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g.,6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG], Azathioprine,Acyclovir, Ganciclovir, Chlorodeoxyadenosine, 2-Chlorodeoxyadenosine[CdA], and 2′-Deoxycoformycin [Pentostatin], etc.), pyrimidineantagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil),5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosinearabinosides (e.g., Cytosar [ara-C] and Fludarabine, etc.); 5) enzymes,including, L-asparaginase; 6) hormones, including, glucocorticoids, suchas, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens(e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole[Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin andCarboplatin, etc.); 8) monoclonal antibodies conjugated with anticancerdrugs, toxins, and/or radionuclides, etc.; 9) biological responsemodifiers (e.g., interferons [e.g., IFN-.alpha., etc.] and interleukins[e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoieticgrowth factors; 12) agents that induce tumor cell differentiation (e.g.,all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14)antisense therapy techniques; 15) tumor vaccines; 16) therapies directedagainst tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors ofangiogenesis.

The pharmaceutical composition and method of the present invention mayfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions. Examples of other therapeutic agents includethe following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodiessuch as ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2,anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, agents blocking theinteraction between CD40 and gp39, such as antibodies specific for CD40and/or gp39 (i.e., CD154), fusion proteins constructed from CD40 andgp39 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocationinhibitors, of NF-kappa B function, such as deoxyspergualin (DSG),cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors(lovastatin and simvastatin), non-steroidal antiinflammatory drugs(NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such asrofecoxib, steroids such as prednisone or dexamethasone, gold compounds,antiproliferative agents such as methotrexate, FK506 (tacrolimus,Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprineand cyclophosphamide, TNF-a inhibitors such as tenidap, anti-TNFantibodies or soluble TNF receptor, and rapamycin (sirolimus orRapamune) or derivatives thereof.

Other agents that may be administered in combination with inventioncompounds include protein therapeutic agents such as cytokines,immunomodulatory agents and antibodies. As used herein the term“cytokine” encompasses chemokines, interleukins, lymphokines, monokines,colony stimulating factors, and receptor associated proteins, andfunctional fragments thereof. As used herein, the term “functionalfragment” refers to a polypeptide or peptide which possesses biologicalfunction or activity that is identified through a defined functionalassay.

The cytokines include endothelial monocyte activating polypeptide II(EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF),macrophage-CSF (M-CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12, andIL-13, interferons, and the like and which is associated with aparticular biologic, morphologic, or phenotypic alteration in a cell orcell mechanism.

When other therapeutic agents are employed in combination with thecompounds of the present invention they may be used for example inamounts as noted in the Physician Desk Reference (PDR) or as otherwisedetermined by one having ordinary skill in the art.

In the treatment or prevention of conditions which involve cellularproliferation, an appropriate dosage level can generally be betweenabout 0.01 and about 1000 mg per 1 kg of patient body weight per daywhich can be administered in single or multiple doses. For example, thedosage level can be between about 0.01 and about 250 mg/kg per day; morenarrowly, between about 0.5 and about 100 mg/kg per day. A suitabledosage level can be between about 0.01 and about 250 mg/kg per day,between about 0.05 and about 100 mg/kg per day, or between about 0.1 andabout 50 mg/kg per day, or about 1.0 mg/kg per day. For example, withinthis range the dosage can be between about 0.05 and about 0.5 mg/kg perday, or between about 0.5 and about 5 mg/kg per day, or between about 5and about 50 mg/kg per day. For oral administration, the compositionscan be provided in the form of tablets containing between about 1.0 andabout 1,000 mg of the active ingredient, for example, about 1.0, about5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0,about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about900.0, and about 1,000.0 mg of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds canbe administered on a regimen of 1 to 4 times per day, such as once ortwice per day. There may be a period of no administration followed byanother regimen of administration.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

Compounds of the present invention can be used, alone or in combinationwith an effective amount of a therapeutic antibody (or therapeuticfragment thereof), a chemotherapeutic or an immunotoxic agent, fortreatment of tumors. Illustrative examples of chemotherapeutic agentsthat can be used for this purpose include doxorubicin, docetaxel, ortaxol. It should be further understood that the invention includescombination therapy including a compound of the invention, including butnot limited to vasculostatic agents, such as tyrosine, serine orthreonine kinase inhibitors, and any chemotherapeutic agent ortherapeutic antibody.

C. EXAMPLES

The following examples are provided to further illustrate the advantagesand features of the present invention, but are not intended to limit thescope of the invention.

Example 1 General Methods

All experiments were performed under anhydrous conditions (i.e. drysolvents) in an atmosphere of argon, except where stated, usingoven-dried apparatus and employing standard techniques in handlingair-sensitive materials. Aqueous solutions of sodium bicarbonate(NaHCO₃) and sodium chloride (brine) were saturated. Analytical thinlayer chromatography (TLC) was carried out on Merck Kieselgel 60 F₂₅₄plates with visualization by ultraviolet and/or anisaldehyde, potassiumpermanganate or phosphomolybdic acid dips. Reverse-phase HPLCchromatography was carried out on Gilson 215 liquid handler equippedwith Waters Symmetry Shield™ RP18 7 μm (40×100 mm) Prep-Pak cartridge.Mobile phase consisted of standard acetonitrile (ACN) and DI Water, eachwith 0.1% TFA added. Purification was carried out at a flow rate of 40mL/min. NMR spectra: ¹H Nuclear magnetic resonance spectra were recordedat 500 MHz. Data are presented as follows: chemical shift, multiplicity(s=singlet, d=doublet, t=triplet, q=quartet, qn=quintet, dd=doublet ofdoublets, m=multiplet, br s=broad singlet), coupling constant (J/Hz) andintegration. Coupling constants were taken directly from the spectra andare uncorrected. Low resolution mass spectra: Electrospray (ES+)ionization was used. The protonated parent ion (M+H) or fragment ofhighest mass is quoted. Analytical gradient consisted of 10% ACN inwater ramping up to 100% ACN over 5 min unless otherwise stated.

Example 2 N⁴-(4-Methoxy-phenyl)-pyrimidine-2,4-diamine (Intermediate 1)

A mixture of 4-chloro-pyrimidin-2-ylamine (0.30 g, 2.3 mmol) and4-methoxy-phenylamine (0.30 g, 2.4 mmol) were suspended in acetic acid(10 mL) and heated at 100° C. for 2 h. The mixture was allowed to coolto room temperature and acetic acid removed under reduced pressure. Theresidue was taken in water (20 mL) and neutralized to pH˜7 with 7M ofNaOH solution. The resulting solution was extracted with EtOAc (30 mL)and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and the crude product purified by flash chromatography on silicagel (hexane to EtOAc) to afford the title intermediate 1 (0.23 g, 45%)as a white solid. ¹H NMR (500 MHz, DMSO-d₆): 3.69 (s, 3H), 5.84 (d,J=5.8 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 7.63 (d, J=9.1 Hz, 2H), 7.78 (d,J=5.8 Hz, 1H), 8.65 (s, 1H); MS (ESI+): m/z 217 (M+H)⁺.

Example 3N⁴-(4-Methoxy-phenyl)-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound I)

To synthesize compound I, intermediate 1 described above andintermediate 2 were used. Intermediate 2,1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine, shown below is availablecommercially, and was used as received.

A suspension of intermediate 1 (74 mg, 0.34 mmol), intermediate 2 (0.10g, 0.37 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol), Xantphos (26 mg, 0.05 mmol)and potassium tert-butoxide (80 mg, 0.71 mmol) in dioxane/DMF (3/1; 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 15 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered and the filteredsolid washed with DCM. The filtrate was concentrated and the residuepurified by HPLC to afford the title compound I (20 mg of TFA salt, 11%)as a brown solid. ¹H NMR (500 MHz, DMSO-d₆): 1.80-1.95 (m, 2H),1.95-2.10 (m, 2H), 3.05-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H),4.29 (t, J=4.9 Hz, 2H), 6.30 (d, J=6.8 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H),6.98 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H),7.89 (d, J=6.2 Hz, 1H), 9.87 (br s, 1H), 10.22 (br s, 1H), 10.44 (br s,1H); MS (ESI+): m/z 406 (M+H)⁺.

Example 44-[4-(4-Methoxy-phenylamino)-pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide(Compound II)

To synthesize compound II, intermediate 1 described above andintermediate 3 were used. Intermediate 3,4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, the formula ofwhich is shown below, was synthesized from 4-bromophenylsulfonylchlorideand 2-aminoethylpyrrolidine, using commonly known synthetic techniques.

A suspension of intermediate 1 described above (70 mg, 0.32 mmol),intermediate 3 (0.12 g, 0.36 mmol), Pd(OAc)₂ (5 mg, 0.022 mmol),Xantphos (26 mg, 0.05 mmol) and potassium tert-butoxide (80 mg, 0.71mmol) in dioxane/DMF (3/1; 4 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 160° C. for 15 min. After cooling toroom temperature, the cap was removed and the resulting mixture filteredand the filtered solid washed with DCM. The filtrate was concentratedand the residue purified by HPLC to afford the title compound II (0.16 gof TFA salt, 85%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): 1.80-1.95(m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.23 (q, J=5.8 Hz, 2H),3.50-3.60 (m, 2H), 3.79 (s, 3H), 6.41 (d, J=6.8 Hz, 1H), 6.99 (d, J=8.9Hz, 2H), 7.43 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.85-7.95 (m,2H), 7.96 (t, J=6.1 Hz, 1H), 8.02 (d, J=6.2 Hz, 1H), 9.64 (br s, 1H),10.21 (br s, 1H), 10.71 (br s, 1H); MS (ESI+): m/z 469 (M+H)⁺.

Example 54-[4-(4-Hydroxy-phenylamino)-pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide(Compound III)

To a solution of compound II described above (50 mg, 0.09 mmol) in DCM(6 mL) at room temperature was added BBr₃ (0.1 mL) and the mixturestirred at room temperature for 2.5 h. The reaction was quenched withsaturated NaHCO₃ solution until the pH˜7 and the mixture extracted withEtOAc (30 mL). The organic layer was separated and washed with brine,dried over MgSO₄ and filtered. The filtrate was concentrated and theresulting solid re-dissolved in minimum of EtOAc. Hexane was added untilsolid crushed out and the title compound III was filtered as a whitesolid (25 mg, 64%) without further purification. ¹H NMR (500 MHz,DMSO-d₆): 1.55-1.65 (m, 4H), 2.30-2.40 (m, 4H), 2.43 (t, J=7.0 Hz, 2H),2.82 (t, J=6.6 Hz, 2H), 6.20 (d, J=5.8 Hz, 1H), 6.70 (d, J=8.8 Hz, 2H),7.40 (d, J=8.6 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.92 (d, J=8.4 Hz, 2H),8.03 (d, J=5.5 Hz, 1H), 8.93 (s, 1H), 9.08 (br s, 1H), 9.70 (s, 1H); MS(ESI+): m/z 455 (M+H)⁺.

Example 64-(4-Chloro-pyrimidin-2-ylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide(Intermediate 4)

A mixture of 4-chloro-pyrimidin-2-ylamine (1.0 g, 7.8 mmol),above-described intermediate 3 (2.6 g, 7.8 mmol), Pd(OAc)₂ (90 mg, 0.40mmol), Xantphos (0.50 g, 0.86 mmol) and potassium tert-butoxide (2.2 g,20 mmol) were suspended in dioxane (30 mL) and heated at reflux underthe argon atmosphere for 16 h. The mixture was poured into water (30 mL)and extracted with EtOAc (60 mL). The organic layer was separated andwashed with brine, dried over MgSO₄ and filtered. The filtrate wasconcentrated in vacuo and the crude product purified by flashchromatography on silica gel (DCM to 25% MeOH/DCM) to afford the titleintermediate 4 (0.15 g, 5%) as a brown solid. MS (ESI+): m/z 382 (M+H)⁺.

Example 74-[4-(3-Methoxy-phenylamino)-pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide(Compound IV)

A mixture of the above described intermediate 4 (0.10 g, 0.26 mmol) and3-methoxy-phenylamine (0.05 mL, 0.45 mmol) were suspended in acetic acid(6 mL) and heated at 100° C. for 1.5 h. The mixture was allowed to coolto room temperature and acetic acid removed under reduced pressure. Theresidue was taken in water (20 mL) and neutralized to pH˜7. Theresulting solution was extracted with EtOAc (30 mL) and the organiclayer separated. The organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by HPLC to afford the title compound IV (55 mg of TFAsalt, 36%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): 1.80-1.90 (m,2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.24 (q, J=6.0 Hz, 2H),3.50-3.60 (m, 2H), 3.73 (s, 3H), 6.40 (d, J=6.3 Hz, 1H), 6.68 (d, J=7.3Hz, 1H), 7.18 (d, J=8.2 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.30 (s, 1H),7.72 (d, J=8.9 Hz, 2H), 7.91 (t, J=6.1 Hz, 1H), 7.95 (d, J=8.7 Hz, 2H),8.10 (d, J=6.2 Hz, 1H), 9.59 (br s, 1H), 9.87 (br s, 1H), 10.38 (br s,1H); MS (ESI+): m/z 469 (M+H)⁺.

Example 84-[4-(3-Hydroxy-phenylamino)-pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide(Compound V)

To a solution of the above-described compound IV (30 mg, 0.05 mmol) inDCM (6 mL) at room temperature was added BBr₃ (0.1 mL) and the mixturestirred at room temperature for 2.5 h. The reaction was quenched withsaturated NaHCO₃ solution until the pH˜7 and the mixture extracted withEtOAc (30 mL). The organic layer was separated and washed with brine,dried over MgSO₄ and filtered. The filtrate was concentrated and theresidue purified by HPLC to afford the title compound V (13 mg of TFAsalt, 46%) as an off white solid. ¹H NMR (500 MHz, DMSO-d₆): 1.80-1.90(m, 2H), 1.95-2.05 (m, 2H), 2.95-3.05 (m, 4H), 3.20-3.30 (m, 2H), 6.39(d, J=6.3 Hz, 1H), 6.53 (d, J=7.2 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 7.09(s, 1H), 7.14 (t, J=8.1 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H), 7.90 (t, J=6.2Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 8.08 (d, J=6.4 Hz, 1H), 9.48 (br s,1H), 9.57 (br s, 1H), 9.86 (br s, 1H), 10.41 (br s, 1H); MS (ESI+): m/z455 (M+H)⁺.

Example 9 Benzo[1,3]dioxol-5-yl-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 5)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),5-bromo-benzo[1,3]dioxole (0.45 g, 2.2 mmol), Pd(OAc)₂ (30 mg, 0.13mmol), Xantphos (0.15 g, 0.26 mmol) and potassium tert-butoxide (0.45 g,4.0 mmol) were suspended in dioxane (15 mL) and heated at reflux underthe argon atmosphere for 16 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (20 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 50% EtOAc/hexane) to afford thetitle intermediate 5 (0.10 g, 18%) as a white solid. MS (ESI+): m/z 264(M+H)⁺.

Example 10N⁴-Benzo[1,3]dioxol-5-yl-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound VI)

To synthesize compound VI, intermediate 5 described above andintermediate 6 were used. Intermediate 6,4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, the formula of which is shownbelow, was synthesized in two steps, first by alkylation of4-nitrophenol using 2-chloroethylpyrrolidine, followed by reduction toyield the aniline derivative.

Commonly known synthetic techniques were used to synthesize intermediate6. A mixture of the above-described intermediate 5 (90 mg, 0.34 mmol),intermediate 6 (95 mg, 0.46 mmol), Pd₂(dba)₃ (20 mg, 0.02 mmol),Xantphos (30 mg, 0.05 mmol) and cesium carbonate (0.30 g, 0.9 mmol) weresuspended in dioxane (10 mL) and heated at reflux under the argonatmosphere for 20 h. The reaction mixture was cooled to room temperatureand diluted with DCM (20 mL). The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound VI (40 mg of TFA salt, 21%) as a brown solid. ¹H NMR (500MHz, DMSO-d₆): 1.85-1.95 (m, 2H), 1.95-2.05 (m, 2H), 2.13 (s, 3H),3.10-3.20 (m, 2H), 4.26 (t, J=5.0 Hz, 2H), 6.07 (s, 2H), 6.90-7.00 (m,4H), 7.19 (s, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.84 (s, 1H), 9.60 (br s,1H), 9.89 (br s, 1H), 10.32 (br s, 1H); MS (ESI+): m/z 434 (M+H)⁺.

Example 11(4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 7)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol),4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd₂(dba)₃ (0.17g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g,7.1 mmol) were suspended in dioxane (20 mL) and heated at reflux underthe argon atmosphere for 5 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 40% EtOAc/hexane) to afford thetitle intermediate 7 (0.55 g, 55%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd, J=8.6 Hz, J=2.3 Hz, 1H),7.39 (d, J=8.7 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 8.09 (d, J=0.9 Hz, 1H),8.91 (s, 1H); MS (ESI+): m/z 284 (M+H)⁺.

Example 12(4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-methyl-amine(Intermediate 8)

A suspension of intermediate 7 (0.50 g, 1.8 mmol) and sodium hydride(60% in mineral oil, 0.15 g, 3.8 mmol) in THF (10 mL) was stirred underthe argon atmosphere at 0° C. for 5 min. Methyl iodide (0.15 mL, 2.4mmol) was syringed at the same temperature to the above mixture. Theresulting solution was stirred from 0° C. to room temperature over 15min and further stirred at room temperature for additional 17 h. Thereaction was quenched with water (10 mL) and then extracted with EtOAc(30 mL). The organic layer was separated and washed with brine, driedover MgSO₄ and filtered. The filtrate was concentrated and the residuepurified by flash chromatography on silica gel (hexane to 20%EtOAc/hexane) to afford the title intermediate 8 (0.20 g, 38%) as awhite solid. MS (ESI+): m/z 298 (M+H)⁺.

Example 13N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(4-chloro-3-methoxyphenyl)-N⁴,5-dimethylpyrimidine-2,4-diamine(Compound VII)

A mixture of intermediate 8 (0.15 g, 0.49 mmol) and intermediate 6 (0.15g, 0.73 mmol), each of which intermediates is described above, weresuspended in acetic acid (8 mL) and heated at 100° C. for 17 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken in water (15 mL) andneutralized to pH˜7 with 7M of NaOH solution. The resulting solution wasextracted with EtOAc (30 mL) and the organic layer separated. Theorganic layer was washed with brine, dried over MgSO₄ and filtered. Thefiltrate was concentrated in vacuo and the crude product purified byHPLC to afford the title compound VII (0.14 g of TFA salt, 49%) as awhite solid. ¹H NMR (500 MHz, DMSO-d₆): 1.85-1.95 (m, 2H), 2.00-2.10 (m,2H), 3.08-3.18 (m, 2H), 3.46 (s, 3H), 3.55-3.65 (m, 4H), 3.85 (s, 3H),4.27 (t, J=5.0 Hz, 2H), 6.86 (d, J=7.4 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H),7.15 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.58 (d, J=8.9 Hz, 2H), 7.83 (s,1H), 9.85 (br s, 1H), 10.04 (br s, 1H), 10.32 (br s, 1H); MS (ESI+): m/z468 (M+H)⁺.

Example 14 (2-Chloro-5-methyl-pyrimidin-4-yl)-(4-chloro-phenyl)-amine(Intermediate 9)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),1-bromo-4-chloro-benzene (0.60 g, 3.1 mmol), Pd₂(dba)₃ (95 mg, 0.10mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0mmol) were suspended in dioxane (20 mL) and heated at reflux under theargon atmosphere for 4 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (20 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 30% EtOAc/hexane) to afford thetitle intermediate 9 (0.15 g, 28%) as a pale yellow solid. MS (ESI+):m/z 254 (M+H)⁺.

Example 15N⁴-(4-Chloro-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound VIII)

A mixture of the above-described intermediates 9 (0.15 g, 0.60 mmol) and6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heated at100° C. for 6 h. The mixture was allowed to cool to room temperature andacetic acid removed under reduced pressure. The residue was taken inwater (15 mL) and neutralized to pH˜7 with 7M of NaOH solution. Theresulting brown solid was filtered and further purified by HPLC toafford the title compound VIII (38 mg of TFA salt, 12%) as a brown oil.¹H NMR (500 MHz, DMSO-d₆): 1.80-1.95 (m, 2H), 2.00-2.10 (m, 2H), 2.15(s, 3H), 3.10-3.20 (m, 2H), 3.55-3.65 (m, 4H), 3.77 (s, 3H), 4.28 (t,J=5.0 Hz, 2H), 6.95 (d, J=9.0 Hz, 2H), 7.38 (d, J=8.9 Hz, 2H), 7.42 (d,J=8.9 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.90 (s, 1H), 9.48 (br s, 1H),9.84 (br s, 1H), 10.10 (br s, 1H); MS (ESI+): m/z 424 (M+H)⁺.

Example 16 2-(4-Amino-phenoxy)-ethanol (Intermediate 10)

A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in MeOH (30mL) was flushed with argon and then charged with Pd/C (10% by wt). Themixture was evacuated under house vacuum and then refilled with hydrogenfrom hydrogen balloon. The cycle was repeated again and the mixturestirred at room temperature for 2 h. The heterogeneous reaction mixturewas filtered through a pad of Celite, washed with MeOH and concentratedin vacuo to furnish the title intermediate 10 (1.8 g, 99%) as a brownsolid. MS (ESI+): m/z 154 (M+H)⁺.

Example 172-{4-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino]-phenoxy}-ethanol(Compound IX)

A suspension of the above described intermediates 7 (50 mg, 0.17 mmol),10 (40 mg, 0.26 mmol), Pd₂(dba)₂ (8 mg, 0.01 mmol), Xantphos (10 mg,0.02 mmol) and cesium carbonate (0.13 g, 0.40 mmol) in dioxane (3 mL)was sealed in a microwave reaction tube and irradiated with microwave at160° C. for 15 min. After cooling to room temperature, the cap wasremoved and the resulting mixture filtered and the filtered solid washedwith DCM. The filtrate was concentrated and the residue purified byflash chromatography on silica gel (hexane to EtOAc) to afford the titlecompound IX (14 mg, 21%) as a light brown solid. ¹H NMR (500 MHz,DMSO-d₆): 2.10 (s, 3H), 3.69 (t, J=5.3 Hz, 2H), 3.75 (s, 3H), 3.92 (t,J=5.1 Hz, 2H), 4.83 (t, J=5.6 Hz, 1H), 6.78 (d, J=9.0 Hz, 2H), 7.29 (d,J=8.5 Hz, 1H), 7.43 (dd, J=8.6 Hz, J=2.2 Hz, 1H), 7.48 (d, J=2.3 Hz,1H), 7.52 (d, J=9.0 Hz, 2H), 7.88 (s, 1H), 8.31 (s, 1H), 8.80 (s, 1H);MS (ESI+): m/z 401 (M+H)⁺.

Example 185-Methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Intermediate 11)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.13 g, 0.87 mmol)and the above described intermediate 6 (0.30 g, 1.5 mmol) were suspendedin acetic acid (8 mL) and heated at 100° C. for 2 h. The mixture wasallowed to cool to room temperature and acetic acid removed underreduced pressure. The residue was taken in water (15 mL) and neutralizedto pH˜7 with 7M of NaOH solution. The resulting solid was filtered (30mg) and washed with ether. The filtrate was extracted with EtOAc (30 mL)and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated toafford the additional solid (0.2 g), which were combined with the firstbatch and afforded the title intermediate 11 (0.23 g, 85%) as a lightbrown solid. ¹H NMR (500 MHz, DMSO-d₆): 1.65-1.70 (m, 4H), 1.89 (s, 3H),2.74 (t, J=6.0 Hz, 2H), 3.98 (t, J=6.1 Hz, 2H), 6.30 (s, 2H), 6.78 (d,J=9.1 Hz, 2H), 7.62 (d, J=9.1 Hz, 2H), 7.64 (s, 1H), 8.50 (s, 1H); MS(ESI+): m/z 314 (M+H)⁺.

Example 195-Methyl-N⁴-phenyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound X)

A suspension of the above-described intermediate 11 (25 mg, 0.08 mmol),bromobenzene (0.05 mL, 0.50 mmol), Pd₂(dba)₂ (5 mg, 0.006 mmol),Xantphos (10 mg, 0.02 mmol) and cesium carbonate (70 mg, 0.21 mmol) indioxane (3 mL) was sealed in a microwave reaction tube and irradiatedwith microwave at 160° C. for 15 min. After cooling to room temperature,the cap was removed and the resulting mixture filtered and the filteredsolid washed with DCM. The filtrate was concentrated and the residuepurified by flash chromatography on silica gel (DCM to 30% MeOH/DCM) toafford the title compound X (10 mg, 32%) as alight brown solid. ¹H NMR(500 MHz, DMSO-d₆): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.48-2.58 (m, 4H),2.75-2.82 (m, 2H), 4.00 (t, J=5.9 Hz, 2H), 6.77 (d, J=9.0 Hz, 2H), 7.04(t, J=7.3 Hz, 1H), 7.32 (t, J=7.9 Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 7.71(d, J=7.8 Hz, 2H), 7.84 (s, 1H), 8.20 (s, 1H), 8.76 (s, 1H); MS (ESI+):m/z 390 (M+H)⁺.

Example 20(4-Chloro-3-fluoro-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 12)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol),4-Bromo-1-chloro-2-fluoro-benzene (1.0 g, 4.8 mmol), Pd₂(dba)₃ (0.16 g,0.17 mmol), Xantphos (0.20 g, 0.34 mmol) and cesium carbonate (2.3 g,7.0 mmol) were suspended in dioxane (25 mL) and heated at reflux underthe argon atmosphere for 15 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 40% EtOAc/hexane) to afford thetitle intermediate 12 (0.75 g, 80%) as an off white solid. MS (ESI+):m/z 272 (M+H)⁺.

Example 21N⁴-(4-Chloro-3-fluoro-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound XI)

A mixture of the above-described intermediates 12 (0.20 g, 0.74 mmol)and 6 (0.20 g, 0.97 mmol) was suspended in acetic acid (8 mL) and heatedat 100° C. for 6 h. The mixture was allowed to cool to room temperatureand acetic acid removed under reduced pressure. The residue was taken inwater (15 mL) and neutralized to pH˜7 with 7M of NaOH solution. Theresulting solution was extracted with EtOAc (30 mL) and the organiclayer separated. The organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by flash chromatography on silica gel (DCM to 30%MeOH/DCM) to afford the title compound XI (90 mg, 28%) as a white solid.¹H NMR (500 MHz, DMSO-d₆): 1.65-1.71 (m, 4H), 2.10 (s, 3H), 2.45-2.55(m, 4H), 2.77 (t, J=6.0 Hz, 2H), 4.01 (t, J=6.0 Hz, 2H), 6.82 (d, J=9.0Hz, 2H), 7.44 (t, J=8.8 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.55 (dd, J=8.9Hz, J=2.0 Hz, 1H), 7.91 (s, 1H), 8.07 (dd, J=12.5 Hz, J=2.0 Hz, 1H),8.43 (s, 1H), 8.90 (s, 1H); MS (ESI+): m/z 442 (M+H)⁺.

Example 22N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound XII)

A suspension of the above-described intermediate 7 (50 mg, 0.17 mmol),4-morpholin-4-ylmethyl-phenylamine (50 mg, 0.26 mmol), Pd₂(dba)₂ (8 mg,0.009 mmol), Xantphos (10 mg, 0.02 mmol) and cesium carbonate (0.13 g,0.40 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube andirradiated with microwave at 160° C. for 15 min. After cooling to roomtemperature, the cap was removed and the resulting mixture filtered andthe filtered solid washed with DCM. The filtrate was concentrated andthe residue purified by HPLC to afford the title compound XII (40 mg ofTFA salt, 43%) as a pale yellow solid. ¹H NMR (500 MHz, DMSO-d₆): 2.16(s, 3H), 3.05-3.15 (m, 2H), 3.10-3.20 (m, 2H), 3.60-3.70 (m, 2H),3.90-4.00 (m, 2H), 4.28 (s, 2H), 4.01 (t, J=6.0 Hz, 2H), 7.25-7.35 (m,3H), 7.35-7.41 (m, 2H), 7.65 (d, J=8.3 Hz, 2H), 7.98 (s, 1H), 9.10 (brs, 1H), 9.86 (br s, 1H), 9.95 (br s, 1H); MS (ESI+): m/z 440 (M+H)⁺.

Example 23Benzo[b]thiophen-5-yl-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 13)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),5-bromo-benzo[b]thiophene (0.6 g, 2.8 mmol), Pd₂(dba)₃ (95 mg, 0.10mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0mmol) was suspended in dioxane (25 mL) and heated at reflux under theargon atmosphere for 3 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 30% EtOAc/hexane) to afford thetitle intermediate 13 (0.23 g, 40%) as a white solid. MS (ESI+): m/z 276(M+H)⁺.

Example 24N⁴-Benzo[b]thiophen-5-yl-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound XIII)

A mixture of the above-described intermediates 13 (0.23 g, 0.83 mmol)and 6 (0.35 g, 1.7 mmol) were suspended in acetic acid (8 mL) and heatedat 100° C. for 1 d. The mixture was allowed to cool to room temperatureand acetic acid removed under reduced pressure. The residue was taken inwater (15 mL) and neutralized to pH˜7 with 7M of NaOH solution. Theresulting solution was extracted with EtOAc (30 mL) and the organiclayer separated. The organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by flash chromatography on silica gel (DCM to 15%MeOH/DCM) to afford the title compound XIII (0.13 g, 35%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆): 1.65-1.75 (m, 4H), 2.12 (s, 3H),2.50-2.62 (m, 4H), 2.75-2.85 (m, 2H), 3.99 (t, J=5.9 Hz, 2H), 6.70 (d,J=9.0 Hz, 2H), 7.36 (d, J=5.4 Hz, 1H), 7.51 (d, J=9.1 Hz, 2H), 7.61 (dd,J=8.7 Hz, J=2.0 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.85 (d, J=0.8 Hz, 1H),7.92 (d, J=8.6 Hz, 1H), 8.29 (d, J=1.7 Hz, 1H), 8.34 (s, 1H), 8.76 (s,1H); MS (ESI+): m/z 446 (M+H)⁺.

Example 25Benzo[b]thiophen-3-yl-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 14)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),3-bromo-benzo[b]thiophene (0.6 g, 2.8 mmol), Pd₂(dba)₃ (95 mg, 0.10mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0mmol) were suspended in dioxane (25 mL) and heated at reflux under theargon atmosphere for 3 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 30% EtOAc/hexane) to afford thetitle intermediate 14 (65 mg, 11%) as a yellow solid. MS (ESI+): m/z 276(M+H)⁺.

Example 26N⁴-Benzo[b]thiophen-3-yl-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound XIV)

A mixture of the above-described intermediates 14 (50 mg, 0.18 mmol) and6 (0.10 g, 0.48 mmol) was suspended in acetic acid (8 mL) and heated at100° C. for 15 h. The mixture was allowed to cool to room temperatureand acetic acid removed under reduced pressure. The residue was taken inwater (10 mL) and neutralized to pH˜7 with 7M of NaOH solution. Theresulting solution was extracted with EtOAc (20 mL) and the organiclayer separated. The organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by flash chromatography on silica gel (DCM to 15%MeOH/DCM) to afford the title compound XIV (10 mg, 13%) as an off whitesolid. ¹H NMR (500 MHz, DMSO-d₆): 1.70-1.80 (m, 4H), 2.19 (s, 3H),2.65-2.80 (m, 4H), 2.85-3.00 (m, 2H), 3.98-4.03 (m, 2H), 6.63 (d, J=8.8Hz, 2H), 7.37 (d, J=8.6 Hz, 2H), 7.38-7.45 (m, 2H), 7.79-7.83 (m, 1H),7.87 (s, 1H), 7.90-8.03 (m, 1H), 8.33 (s, 1H), 8.78 (s, 1H); MS (ESI+):m/z 446 (M+H)⁺.

Example 27 (2-Chloro-5-methyl-pyrimidin-4-yl)-(3-chloro-phenyl)-amine(Intermediate 15)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),1-bromo-3-chloro-benzene (0.60 g, 3.1 mmol), Pd₂(dba)₃ (95 mg, 0.10mmol), Xantphos (0.12 g, 0.20 mmol) and cesium carbonate (1.3 g, 4.0mmol) was suspended in dioxane (20 mL) and heated at reflux under theargon atmosphere for 4 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (20 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexane to 40% EtOAc/hexane) to afford thetitle intermediate 15 (0.30 g, 56%) as a pale yellow solid. MS (ESI+):m/z 254 (M+H)⁺.

Example 28N⁴-(3-Chloro-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound XV)

A mixture of the above-described intermediates 15 (0.15 g, 0.59 mmol)and 6 (0.25 g, 1.2 mmol) was suspended in acetic acid (8 mL) and heatedat 100° C. for 21 h. The mixture was allowed to cool to room temperatureand acetic acid removed under reduced pressure. The residue was taken inwater (15 mL) and neutralized to pH˜7 with 7M of NaOH solution. Theresulting solution was extracted with EtOAc (30 mL) and the organiclayer separated. The organic layer was washed with brine, dried overMgSO₄ and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by flash chromatography on silica gel (DCM to 10%MeOH/DCM) to afford the title compound XV (60 mg, 24%) as a white solid.¹H NMR (500 MHz, DMSO-d₆): 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.50-2.60(m, 4H), 2.78-2.83 (m, 2H), 4.01 (t, J=5.9 Hz, 2H), 6.81 (d, J=9.1 Hz,2H), 7.05-7.08 (m, 1H), 7.32 (t, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 2H),7.71 (d, J=8.3 Hz, 1H), 7.85 (t, J=2.1 Hz, 1H), 7.89 (d, J=0.7 Hz, 1H),8.33 (s, 1H), 8.86 (s, 1H); MS (ESI+): m/z 424 (M+H)⁺.

Example 29 3-Bromo-N-methyl-benzamide (Intermediate 16)

A solution of 3-bromo-benzoyl chloride (2.93 g, 13.3 mmol, 1 eq) in 30mL THF was stirred vigorously and treated with 2.0M methylamine in THF(15 mL, 29.4 mmol, 2.2 eq). A white precipitate was observed and thereaction was allowed to stir for 20 minutes. Reaction was then pouredonto ethyl acetate (100 mL) and washed with water (2×150 mL) and brine(1×150 mL). Organic phase cut from aqueous phase and dried over sodiumsulfate, filtered and evaporated to afford the title intermediate 16 asa white powder. (2.29 g, 82% yield).

Example 30 3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-N-methyl-benzamide(Intermediate 17)

In a dry 50 mL round bottom flask, 2-chloro-5-methyl-pyrimidin-4-ylamine(0.3 g, 2.09 mmol, 1 equiv), 3-bromo-N-methyl-benzamide (0.489 g, 2.29mmol, 1.1 equiv), cesium carbonate (2.04 g, 6.27 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.242 g, 0.418 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.191 g, 0.209mmol, 0.1 equiv) were combined. Reactants were diluted with dioxane (20mL), flushed with argon and outfitted with reflux condenser. Reactionwas heated to reflux for 16 hours. Reaction was then transferred intocentrifuge tube, spun down, decanted and evaporated. Resulting yellowsolids were diluted with DCM and adsorbed onto silica gel.Chromatography (gradient of 50% ethyl acetate in hexanes up to 100%ethyl acetate) afforded the title intermediate 17 as a pale yellowpowder (0.25 g, 43% yield). MS (ESI+): 277.01 (M+H), r.t.=1.92 min.

Example 31N-Methyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzamideTFA salt (Compound XVI)

The above-described intermediate 17 (0.068 g, 0.246 mmol, 1 eq),4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.061 g, 0.296 mmol, 1.2 eq),cesium carbonate (0.241 g, 0.74 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.029 g, 0.05 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.023 g, 0.025mmol, 0.1 equiv) were combined in 15 ml microwave vessel. Reactants werethen diluted with 7 ml dioxane and microwaved for 15 minutes at 160° C.Reaction vessel was then spun down, decanted and evaporated to dryness.HPLC purification afforded the TFA salt of the title product XVI (0.084g, 76%). MS (ESI+): 447.20 (M+H), r.t.=1.53 min. ¹H NMR (DMSO-d₆): δ1.87-1.91 (m, 2H), 2.02-2.06 (m, 2H), 2.16 (s, 3H), 2.79 (d, J=4.6 Hz,3H), 3.11-3.15 (m, 2H), 3.57-3.61 (m, 5H), 4.23 (t, J=5.0 Hz, 3H), 6.84(d, J=8.8 Hz, 2H), 7.34 (d, J=8.9 Hz, 2H), 7.47 (t, J=7.9 Hz, 1H),7.68-7.70 (m, 2H), 7.93 (s, 1H), 8.00 (s, 1H), 8.46-8.47 (m, 1H), 9.80(bs, 1H), 9.93 (bs, 1H) 10.41 (bs, 1H).

Example 32N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamineTFA salt (Compound XVII)

The above-described intermediate 7 (0.083 g, 0.293 mmol, 1 eq),4-(2-Pyrrolidin-1-yl-ethoxy)-phenylamine (0.073 g, 0.352 mmol, 1.2 eq),cesium carbonate (0.287 g, 0.879 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.034 g, 0.059 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.027 g, 0.029mmol, 0.1 equiv) were combined in 15 ml microwave vessel. Reactants werethen diluted with 7 ml dioxane and microwaved for 15 minutes at 160° C.Reaction vessel was then spun down, decanted and evaporated to dryness.HPLC purification afforded the TFA salt of the title product XVII (0.1g, 75%). MS (ESI+): 454.13 (M+H), r.t.=1.82 min. ¹H NMR (DMSO-d₆): δ1.87-1.90 (m, 2H), 2.02-2.05 (m, 2H), 2.15 (s, 3H), 3.11-3.14(m, 2H),3.58-3.61 (m, 5H), 3.70 (s, 3H), 4.26 (t, J=5.0 Hz, 3H), 6.91 (d, J=8.9Hz, 2H), 7.23 (m, 1H), 7.34-7.4 (m, 4H), 7.93 (s, 1H), 9.63 (bs, 1H),9.96 (bs, 1H) 10.40 (bs, 1H).

Example 33N-(2-Chloro-5-methyl-pyrimidin-4-yl)-N′,N′-dimethyl-benzene-1,3-diamine(Intermediate 18)

2-Chloro-5-methyl-pyrimidin-4-ylamine (0.343 g, 2.38 mmol, 1 equiv),(3-bromo-phenyl)-dimethyl-amine (0.524 g, 2.62 mmol, 1.1 equiv), cesiumcarbonate (2.3 g, 7.15 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.276 g, 0.476 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.218 g, 0.238mmol, 0.1 equiv) were combined in 30 ml microwave vessel. Reactants werethen diluted with 12 ml dioxane and microwaved for 25 minutes at 160° C.Reaction vessel was then spun down, decanted and evaporated to dryness.Resulting solids were diluted with DCM and adsorbed onto silica gel.Chromatography (gradient of 0% methanol in DCM up to 25% methanol inDCM) afforded the title intermediate 18 as orange solid (0.184 g, 29%yield). MS (ESI+): 263.02 (M+H), r.t.=1.72 min.

Example 34N⁴-(3-Dimethylamino-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamineTFA salt (Compound XVIII)

The above-described intermediate 18 (0.092 g, 0.35 mmol, 1 eq),4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.087 g, 0.42 mmol, 1.2 eq),cesium carbonate (0.343 g, 1.05 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.041 g, 0.0702 mmol, 0.2 equiv) andtris(dibenzylideneacetone) dipalladium (0.032 g, 0.035 mmol, 0.1 equiv)were combined in a 15 ml microwave vessel. Reactants were then dilutedwith 7 ml dioxane and microwaved for 15 minutes at 160° C. Reactionvessel was then spun down, decanted and evaporated to dryness. HPLCpurification provided the TFA salt of the title compound XVIII (0.035 g,23%). MS (ESI+): 433.21 (M+H), r.t.=1.52 min. ¹H NMR (DMSO-d₆): δ1.87-1.90 (m, 2H), 2.03-2.06 (m, 2H), 2.15 (s, 3H), 2.87 (s, 6H),3.12-3.15 (m, 2H), 3.57-3.60 (m, 4H), 3.70 (s, 3H), 4.25 (t, J=5.0 Hz,3H), 6.34 (dd, J=8.4 Hz, J=2.3 Hz, 1H), 6.82-6.90 (m, 4H), 7.20 (t,J=8.0 Hz, 1H), 7.39 (d, J=9.1 Hz, 2H), 7.85 (s, 1H), 9.63 (bs, 1H), 9.90(bs, 1H) 10.39 (bs, 1H).

Example 35(2-Chloro-5-methyl-pyrimidin-4-yl)-(3,4-dichloro-phenyl)-amine(Intermediate 19)

2-chloro-5-methyl-pyrimidin-4-ylamine (0.408 g, 2.83 mmol, 1 equiv),4-Bromo-1,2-dichloro-benzene (0.704 g, 3.12 mmol, 1.1 equiv), cesiumcarbonate (2.8 g, 8.49 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.328 g, 0.57 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.26 g, 0.283mmol, 0.1 equiv) were combined in 30 ml microwave vessel. Reactants werethen diluted with 12 ml dioxane and microwaved for 25 minutes at 160° C.Reaction vessel was then spun down, decanted and evaporated to dryness.Resulting solids were diluted with DCM and adsorbed onto silica gel.Chromatography (gradient of 15% ethyl acetate in hexanes up to 80% ethylacetate in hexanes) afforded the title intermediate 19 as a pale yellowpowder (0.366 g, 45% yield). MS (ESI+): 287.97 (M+H), r.t.=3.12 min.

Example 36N⁴-(3,4-Dichloro-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamineTFA salt (Compound XIX)

The above-described intermediate 19 (0.09 g, 0.313 mmol, 1 eq),4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.078 g, 0.376 mmol, 1.2 eq),cesium carbonate (0.307 g, 0.941 mmol, 3 equiv),4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.036 g, 0.063 mmol,0.2 equiv) and tris(dibenzylideneacetone) dipalladium (0.029 g, 0.0314mmol, 0.1 equiv) were combined in 15 ml microwave vessel. Reactants werethen diluted with 7 ml dioxane and microwaved for 15 minutes at 160° C.Reaction vessel was then spun down, decanted and evaporated to dryness.HPLC purification provided the TFA salt of the title compound XIX (0.056g, 39%). MS (ESI+): 458.1 (M+H), r.t.=1.93 min. ¹H NMR (DMSO-d₆): δ1.87-1.91 (m, 2H), 2.03-2.06 (m, 2H), 2.14 (s, 3H), 3.12-3.15 (m, 3H),3.57-3.60 (m, 4H), 4.26 (t, J=5.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.40(d, J=9 Hz, 2H), 7.60 (s, 2H), 7.97 (d, J=15.35 Hz, 2H), 9.46 (bs, 1H),9.89 (bs, 1H) 10.17 (bs, 1H).

Example 374-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (Intermediate 20)

(4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(0.092 g, 0.325 mmol, 1 eq), 4-(3-amino-benzyl)-piperazine-1-carboxylicacid tert-butyl ester (0.114 g, 0.39 mmol, 1.2 eq), cesium carbonate(0.318 g, 0.975 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.038 g, 0.065 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.03 g, 0.0325 mmol, 0.1 equiv) were combined in a 15 mlmicrowave vessel. Reactants were then diluted with 7 ml dioxane andmicrowaved for 15 minutes at 160° C. Reaction vessel was then spun down,decanted and evaporated to dryness. HPLC purification afforded the TFAsalt of the title intermediate 20 (0.075 g, 43%). MS (ESI+): 539.32(M+H), r.t.=2.09 min.

Example 38N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(3-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamineTFA salt (Compound XX)

A stirring solution of the above-described intermediate 20 (0.075 g,0.14 mmol, 1 eq) in DCM (6 ml) was treated with TFA (2 ml). After 2 h,reaction solvents were evaporated and resulting residue triturated withether to afford the title compound XX as white, hygroscopic solids, TFAsalt. (0.05 g, 82%). MS (ESI+): 439.13 (M+H), r.t.=1.67 min. ¹H NMR(DMSO-d₆): δ 2.17 (s, 3H), 2.89 (bs, 4H), 3.2 (bs, 4H), 3.68 (s, 3H),3.82 (bs, 3H), 7.16-7.20 (m, 2H), 7.28 (t, J=7.7 Hz, 1H), 7.33 (d, J=2.3Hz, 1H), 7.39 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.98(s, 1H), 8.87 (bs, 1H), 9.79 (bs, 1H) 10.57 (bs, 1H).

Example 392-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenylamino)-4-aminopyrimidine-5-carbonitrile(Intermediate 21)

To a solution of 2,4-diaminopyrimidine-5-carbonitrile (135 mg, 1.00mmol) in 1,4-dioxane (20 mL) was added1-(2-(4-bromophenoxy)ethyl)pyrrolidine (270 mg, 1.0 mmol), Cs₂CO₃ (1.3g, 4.0 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (50 mL) was added, the solid was collectedby filtration. The crude product was purified by HPLC and afforded thetitle intermediate 21 (32 mg, 10%).

Example 404-(2,4-Dichloro-5-methoxyphenylamino)-2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl-amino)pyrimidine-5-carbonitrile(Compound XXI)

To a solution of the above-described intermediate 21 (32 mg, 0.1 mmol)in 1,4-dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene(28 mg, 0.11 mmol), Cs₂CO₃ (97 mg, 0.3 mmol), Pd₂(dba)₃ (7 mg, 0.0074mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 13mg, 0.022 mmol). The mixture was heated under reflux for 4 h under Ar.The solid was filtered off and the filtrate washed with brine (1×50 mL).The organic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by chromatograph(SiO₂/CH₂Cl₂, then CH₂Cl₂:MeOH:NH₃.H₂O=100:10:1) and afforded the titlecompound XXI (35 mg, 67%). ¹H NMR (500 MHz, DMSO-d⁶): 1.88-1.90 (m, 2H);2.00-2.03 (m, 2H); 3.07-3.11 (m, 2H); 3.54-3.56 (m, 4H); 3.81 (s, 3H);4.25 (br, 2H); 6.68 (br, 2H); 7.32 (br, 2H); 7.33 (s, 1H); 7.75 (s, 1H);8.50 (s, 1H); 9.73 (br, 1H); 9.94 (br, 1H); 10.60 (br, 1H). MS (EI):499.0.

Example 412-(3-(2-(Pyrrolidin-1-yl)ethoxy)phenylamino)-4-aminopyrimidine-5-carbonitrile(Intermediate 22)

To a solution of 2,4-diaminopyrimidine-5-carbonitrile (145 mg, 1.07mmol) in 1,4-dioxane (20 mL) was added1-(2-(3-bromophenoxy)ethyl)pyrrolidine (290 mg, 1.07 mmol), Cs₂CO₃ (1.43g, 4.4 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 174 mg, 0.3mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (50 mL) was added, the solid was collectedby filtration. The crude product was purified by HPLC and afforded thetitle intermediate 22 (55 mg, 16%).

Example 424-(2,4-Dichloro-5-methoxyphenylamino)-2-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl-amino)pyrimidine-5-carbonitrile(Compound XXII)

To a solution of the above-described intermediate 22 (50 mg, 0.15 mmol)in 1,4-dioxane (10 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene(44 mg, 0.17 mmol), Cs₂CO₃ (200 mg, 0.62 mmol), Pd₂(dba)₃ (14 mg, 0.015mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 27mg, 0.05 mmol). The mixture was heated under reflux for 4 h under Ar.The solid was filtered off and the filtrate washed with brine (1×50 mL).The organic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXII (6 mg, 8%). ¹H NMR (500 MHz, DMSO-d⁶): 1.87-1.89(m, 2H); 1.90-2.03 (m, 2H); 3.04-3.08 (m, 2H); 3.52-3.56 (m, 4H); 3.80(s, 3H); 4.23 (br, 2H); 6.62 (d, J=6.4 Hz, 2H); 6.97 (br, 1H); 7.14 (br,2H); 7.34 (s, 1H); 7.74 (s, 1H); 8.54 (s, 1H); 9.70 (br, 1H); 9.95 (br,1H); 10.83 (br, 1H). MS (EI): 499.0.

Example 432-Chloro-N-(2,4-dichloro-5-methoxyphenyl)-5-methylpyrimidin-4-amine(Intermediate 23)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol)in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene(96 mg, 0.37 mmol), Cs₂CO₃ (408 mg, 1.25 mmol), Pd₂(dba)₃ (37 mg, 0.04mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar.The solid was filtered off and the filtrate washed with brine (1×100mL). The organic solution was separated and dried (Na₂SO₄). The solventwas removed in vacuo. The crude product was used for next reactionwithout purification.

Example 44N²-(3-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(2,4-dichloro-5-methoxyphenyl)-5-methylpyrimidine-2,4-diamine(Compound XXIII)

To a solution of the above-described intermediate 23 in 1,4-dioxane (10mL) was added 3-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (77.3 mg, 0.38mmol), Cs₂CO₃ (488 mg, 1.25 mmol), Pd₂(dba)₃ (28 mg, 0.03 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 53 mg, 0.09mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXIII (25 mg, 15%). ¹H NMR (500 MHz, DMSO-d⁶):1.87-1.89 (m, 2H); 1.90-2.03 (m, 2H); 2.18 (s, 3H); 3.04-3.08 (m, 2H);3.52-3.56 (m, 4H); 3.80 (s, 3H); 4.24 (t, J=5.0 Hz, 2H); 6.71 (d, J=7.65Hz, 1H); 6.91 (s, 1H); 6.96 (d, J=8.5 Hz, 1H); 7.02 (t, J=8.2 Hz, 1H);7.37 (s, 1H); 7.83 (s, 1H); 8.02 (s, 1H); 10.09 (br, 1H); 10.66 (br,1H); 10.82 (br, 1H). MS (EI): 488.2.

Example 45 2-Chloro-N-(3-methoxyphenyl)-5-methylpyrimidin-4-amine(Intermediate 24)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol)in 1,4-dioxane (40 mL) was added 1-bromo-3-methoxybenzene (458.5 mg,2.45 mmol), Cs₂CO₃ (2.9 g, 8.9 mmol), Pd₂(dba)₃ (201 mg, 0.22 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 382 mg, 0.66mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (100 mL) was added, the solid wascollected by filtration. The crude product, the title intermediate 24(500 mg, 90%), was used for next reaction without further purification.

Example 46N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(3-methoxyphenyl)-5-methyl-pyrimidine-2,4-diamine(Compound XXIV)

To a solution of the above-described intermediate 24 (240 mg, 0.96 mmol)in 1,4-dioxane (20 mL) was added4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (200 mg, 0.96 mmol), Cs₂CO₃(1.3 mg, 4.0 mmol), Pd₂(dba)₃ (82 mg, 0.09 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 156 mg, 0.27mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXIV (85 mg, 20%). ¹H NMR (500 MHz, DMSO-d⁶):1.89-1.91 (m, 2H); 1.98-2.05 (m, 2H); 2.16 (s, 3H); 3.07-3.12 (m, 2H);3.52-3.56 (m, 4H); 3.73 (s, 3H); 4.33 (t, J=4.5 Hz, 2H); 6.83-6.85 (m,1H); 6.91 (d, J=8.8 Hz, 2H); 7.17 (s, 1H); 7.34 (d, J=8.8 Hz, 2H); 7.41(t, J=7.7 Hz, 1H); 7.56 (d, J=7.7 Hz, 1H); 7.89 (s, 1H); 9.75 (s, 1H);10.51 (s, 1H); 10.96 (br, 1H). MS (EI): 420.2.

Example 473-(2-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-phenol(Compound XXV)

To a solution of the above-described compound XXIV (50 mg, 0.1 mmol) inanhydrous CH₂Cl₂ (10 mL) was added 1.0 M BBr₃ in CH₂Cl₂ (0.3 mL, 0.3mmol). The mixture was stirred for 3 h at room temperature. Thesaturated NaHCO₃ (20 mL) was added and organic layer was separated. Theaqueous was extracted with CH₂Cl₂ (3×10 mL). Combined organic solutionwas dried (Na₂SO₄). The product was purified by HPLC and afforded thetitle compound XXV (17 mg, 35%) as yellow solid. ¹H NMR (500 MHz,DMSO-d⁶): 1.89 (br, 2H); 2.00 (br, 2H); 2.14 (s, 3H); 3.09 (br, 2H);3.42 (br, 4H); 4.33 (br, 2H); 6.72 (d, J=7.1 Hz, 1H); 6.91 (d, J=8.4 Hz,2H); 6.96 (d, J=7.6 Hz, 1H); 7.00 (s, 1H); 7.18 (t, J=8.0 Hz, 1H); 7.38(d, J=8.6 Hz, 2H); 7.88 (s, 1H); 9.70 (s, 1H); 9.74 (s, 1H); 10.55 (s,1H); 11.09 (br, 1H). MS (EI): 406.2.

Example 48 2-Chloro-5-methyl-N-(3-nitrophenyl)pyrimidin-4-amine(Intermediate 25)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (232 mg, 1.61 mmol)in 1,4-dioxane (40 mL) was added 1-bromo-3-nitrobenzene (359 mg, 1.78mmol), Cs₂CO₃ (2.1 g, 6.4 mmol), Pd₂(dba)₃ (146 mg, 0.16 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 278 mg, 0.48mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (100 mL) was added, the solid wascollected by filtration. The crude product, the title intermediate 25,was used for next reaction without further purification.

Example 49N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-(3-nitrophenyl)pyrimidine-2,4-diamine(Compound XXVI)

To a solution of the above-described intermediate 25 in 1,4-dioxane (40mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (367 mg, 1.78mmol), Cs₂CO₃ (2.1 g, 6.4 mmol), Pd₂(dba)₃ (146 mg, 0.16 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 218 mg, 0.48mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXVI (51 mg, 7%). ¹H NMR (500 MHz, DMSO-d⁶):1.89-1.92 (m, 2H); 1.98-2.05 (m, 2H); 2.21 (s, 3H); 3.10-3.12 (m, 2H);3.52-3.57 (m, 4H); 4.33 (t, J=4.8 Hz, 2H); 6.90 (d, J=8.9 Hz, 2H); 7.32(d, J=8.9 Hz, 2H); 7.67 (t, J=8.2 Hz, 1H); 7.99 (s, 1H); 7.56 (dd, J=8.4Hz, J=1.8 Hz, 1H); 8.09 (d, J=7.4 Hz, 1H); 8.45 (s, 1H); 10.14 (s, 1H);10.60 (s, 1H); 11.17 (br, 1H). MS (EI): 435.2.

Example 50 4-(2-Chloro-5-methylpyrimidin-4-ylamino)-2-chlorobenzonitrile(Intermediate 26)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol)in 1,4-dioxane (20 mL) was added 4-bromo-2-chlorobenzonitrile (217 mg,1.0 mmol), Cs₂CO₃ (1.3 g, 4.0 mmol), Pd₂(dba)₃ (91 mg, 0.1 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 173 mg, 0.3mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (100 mL) was added, the solid wascollected by filtration. The crude product, the title intermediate 26,was used for next reaction without further purification.

Example 514-(2-(4-(2-(pyrrolidin-1-yl)ethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-2-chlorobenzonitrile(Compound XXVII)

To a solution of the above-described intermediate 26 (140 mg, 0.5 mmol)in 1,4-dioxane (20 mL) was added4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (113 mg, 0.55 mmol), Cs₂CO₃(660 mg, 2.0 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXVII (11.5 mg, 5%) as a yellow solid. ¹H NMR (500MHz, DMSO-d⁶): 1.89-1.92 (m, 2H); 1.98-2.05 (m, 2H); 2.20 (s, 3H);3.08-3.13 (m, 2H); 3.56-3.59 (m, 4H); 4.36 (t, J=4.9 Hz, 2H); 7.03 (d,J=9.0 Hz, 2H); 7.40 (d, J=9.0 Hz, 2H); 7.87 (br, 1H); 7.92 (d, J=8.6 Hz,1H); 8.03 (s, 1H); 8.16 (s, 1H); 9.82 (br, 1H); 10.37 (br, 1H); 10.90(br, 1H). MS (EI): 449.1.

Example 52N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-p-tolylpyrimidine-2,4-diamine(Compound XXVIII)

To a solution of the above-described intermediate 11 (50 mg, 0.16 mmol)in 1,4-dioxane (20 mL) was added 1-bromo-4-methylbenzene (28 mg, 0.16mmol), Cs₂CO₃ (210 mg, 0.64 mmol), Pd₂(dba)₃ (10 mg, 0.01 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 18 mg, 0.03mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off. The solvent was removed in vacuo. The crude productwas purified by HPLC and afforded the title compound XXVIII (15.7 mg,6%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d⁶): 1.85-1.89 (m, 2H);1.96-2.01 (m, 2H); 2.12 (s, 3H); 2.31 (s, 3H); 3.04-3.08 (m, 2H);3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.89 (br, 2H); 7.18 (br, 2H); 7.31(br, 2H); 7.41 (br, 2H); 7.84 (s, 1H); 9.71 (s, 1H); 10.46 (s, 1H);11.13 (br, 1H). MS (EI): 404.2.

Example 53N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(4-chloro-3-methylphenyl)-5-methylpyrimidine-2,4-diamine(Compound XXIX)

To a solution of the above-described intermediate 11 (80 mg, 0.25 mmol)in 1,4-dioxane (20 mL) was added 4-bromo-1-chloro-2-methylbenzene (63mg, 0.30 mmol), Cs₂CO₃ (326 mg, 1.0 mmol), Pd₂(dba)₃ (18 mg, 0.02 mmol),and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 36 mg,0.06 mmol). The mixture was heated under reflux for 4 h under Ar. Thesolid was filtered off. The solvent was removed in vacuo. The crudeproduct was purified by HPLC and afforded the title compound XXIX (17.5mg, 15%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d⁶): 1.85-1.89 (m,2H); 1.96-2.01 (m, 2H); 2.12 (s, 3H); 2.25 (s, 3H); 3.04-3.08 (m, 2H);3.51-3.55 (m, 4H); 4.32 (br, 2H); 6.91 (br, 2H); 7.04 (br, 1H); 7.31(br, 1H); 7.41 (br, 2H); 7.58 (s, 1H); 7.89 (br, 1H); 9.75 (s, 1H);10.54 (s, 1H); 11.13 (br, 1H). MS (EI): 438.1.

Example 54N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-4-benzyl-5-methylpyrimidin-2-amine(Compound XXX)

To a solution of 4-benzyl-2-chloropyrimidine (286 mg, 1.4 mmol) in1,4-dioxane (20 mL) was added 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine(288 mg, 1.4 mmol), Cs₂CO₃ (1.82 g, 5.6 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos,173 mg, 0.3 mmol). The mixture was heated under reflux for 4 h under Ar.The solid was filtered off. The solvent was removed in vacuo. The crudeproduct was purified by HPLC and afforded the title compound XXX (42 mg,10%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d⁶): 1.89 (br, 2H); 2.00(br, 2H); 3.09 (br, 2H); 3.54 (br, 4H); 4.31 (br, 2H); 6.71 (d, J=5.0Hz, 1H); 6.93 (d, J=8.8 Hz, 2H); 7.24 (m, 1H); 7.32 (m, 4H); 7.62 (d,J=8.8 Hz, 2H); 8.32 (d, J=5.0 Hz, 1H); 9.66 (s, 1H); 10.92 (br, 1H). MS(EI): 375.2.

Example 554-((1H-indol-4-yl)methyl)-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methylpyrimidin-2-amine(Compound XXXI)

To a solution of the above-described intermediate 11 (460 mg, 1.46 mmol)in 1,4-dioxane (20 mL) was added 4-bromo-1H-indole (288 mg, 1.46 mmol),Cs₂CO₃ (1.95 g, 6.0 mmol), Pd₂(dba)₃ (128 mg, 0.14 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 243 mg, 0.42mmol). The mixture was heated under reflux for overnight under Ar. Thesolid was filtered off. The solvent was removed in vacuo. The crudeproduct was purified by HPLC and afforded the title compound XXXI (66mg, 10%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d⁶): 1.87 (br, 2H);1.98-2.05 (m, 2H); 2.21 (s, 3H); 3.15 (br, 2H); 3.52 (br, 2H); 3.69 (br,2H), 4.24 (br, 2H); 6.33 (s, 1H); 6.60 (br, 2H); 6.82 (br, 1H); 6.92(br, 1H); 7.02 (br, 2H); 7.16 (br, 1H); 7.26 (br, 1H); 7.43 (m, 1H);7.88 (m, 1H); 10.11 (s, 1H); 11.40 (s, 1H). MS (EI): 429.1.

Example 56 2-Chloro-5-methyl-N-(naphthalen-1-yl)pyrimidin-4-amine(Intermediate 27)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol)in 1,4-dioxane (40 mL) was added 1-bromonaphthalene (227 mg, 1.1 mmol),Cs₂CO₃ (1.3 g, 4.0 mmol), Pd₂(dba)₃ (91 mg, 0.1 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (100 mL) was added, the solid wascollected by filtration. The crude product, the title intermediate 27,was used for next reaction without further purification.

Example 57N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-4-(naphthalen-1-yl)pyrimidin-2-amine(Compound XXXII)

To a solution of the above-described intermediate 27 (235 mg, 0.87 mmol)in 1,4-dioxane (20 mL) was added4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (183 mg, 0.87 mmol), Cs₂CO₃(1.3 g, 4.0 mmol), Pd₂(dba)₃ (46 mg, 0.05 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 87 mg, 0.15mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXXII (89 mg, 21%) as a yellow solid. ¹H NMR (500MHz, DMSO-d⁶): 1.88-1.90 (m, 2H); 1.97-2.03 (m, 2H); 2.30 (s, 3H);3.03-3.08 (m, 2H); 3.50-3.53 (m, 4H); 4.21 (t, J=4.9 Hz, 2H); 6.50 (d,J=7.2 Hz, 2H); 6.82 (d, J=8.6 Hz, 2H); 7.54 (d, J=7.8 Hz, 2H); 7.57-7.61(m, 1H); 7.63 (t, J=7.4 Hz, 1H); 7.89 (d, J=8.3 Hz, 2H); 7.95 (s, 1H);8.02 (d, J=8.3 Hz, 1H); 8.08 (d, J=7.7 Hz, 1H); 10.37 (s, 1H); 10.43 (s,1H); 10.93 (br, 1H). MS (EI): 440.1.

Example 58 1-(2-Chloro-5-methylpyrimidin-4-yl)isoquinoline (Intermediate28)

To a solution of 2-chloro-5-methylpyrimidin-4-amine (144 mg, 1.0 mmol)in 1,4-dioxane (40 mL) was added 1-chloroisoquinoline (164 mg, 1.0mmol), Cs₂CO₃ (1.3 g, 4.0 mmol), Pd₂(dba)₃ (91 mg, 0.1 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 183 mg, 0.3mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×100 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved until 5 mL and hexane (100 mL) was added, the solid wascollected by filtration. The crude product, the title intermediate 28,was used for next reaction without further purification.

Example 59N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-4-(isoquinolin-1-yl)-5-methylpyrimidin-2-amine(Compound XXXIII)

To a solution of the above-described intermediate 28 (90 mg, 0.33 mmol)in 1,4-dioxane (20 mL) was added4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (76 mg, 0.37 mmol), Cs₂CO₃ (391mg, 1.2 mmol), Pd₂(dba)₃ (28 mg, 0.03 mmol), and4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 52 mg, 0.09mmol). The mixture was heated under reflux for 4 h under Ar. The solidwas filtered off and the filtrate washed with brine (1×50 mL). Theorganic solution was separated and dried (Na₂SO₄). The solvent wasremoved in vacuo. The crude product was purified by HPLC and affordedthe title compound XXXIII (21 mg, 15%) as a yellow solid. ¹H NMR (500MHz, DMSO-d⁶): 1.64-1.70 (m, 6H); 2.23 (s, 3H); 2.78 (t, J=5.9 Hz, 2H);4.04 (t, J=5.9 Hz, 2H); 6.38 (d, J=7.2 Hz, 1H); 6.93 (d, J=9.0 Hz, 2H);6.97 (d, J=7.2 Hz, 1H); 7.45 (br, 1H); 7.57 (d, J=8.8 Hz, 1H); 7.58-7.62(m, 1H); 7.70-7.78 (m, 2H); 8.04 (s, 1H); 8.75 (d, J=8.1 Hz, 1H); 9.06(s, 1H); 9.19 (s, 1H). MS (EI): 441.2.

Example 60N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine(Compound XXXIV)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (143 mg, 1.0 mmol),1-bromo-3-(trifluoromethyl)benzene (225 mg, 1.0 mmol), Pd₂(dba)₃ (9.0mg, 0.01 mmol), Xantphos (12 mg, 0.02 mmol) and cesium carbonate (650mg, 2.0 mmol) were suspended in dioxane (15 mL) and heated at refluxunder the argon atmosphere for 15 h. The reaction mixture was cooled toroom temperature and diluted with DCM (30 mL). The mixture was filteredand the filtrate concentrated in vacuo . The residue on purificationusing HPLC gaveN⁴-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine as an offwhite solid (192 mg, 67%). MS (ESI+): m/z 288 (M+H)⁺. A mixture ofN⁴-(3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine (28.7 mg,0.1 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (22 mg, 0.12mmol) were dissolved in acetic acid (5 mL) and heated under microwave at150° C. for 10 min. The mixture was cooled to room temperature andacetic acid removed under reduced pressure. The residue was purified byHPLC to afford the title compound XXXIV as brown solid (16 mg, 35%). ¹HNMR (500 MHz, DMSO-d₆): 1.65-1.71 (m, 4H), 2.11 (s, 3H), 2.45-2.55 (m,4H), 2.74 (t, J=6.0 Hz, 2H), 3.98 (t, J=6.0 Hz, 2H), 6.76 (d, J=9.0 Hz,2H), 7.35 (d, J=5.1 Hz, 1H), 7.45-7.57 (m, 3H), 7.9-7.97 (m, 2H), 8.20(d, J=7.6 Hz, 1H), 8.41(s, 1H), 8.85 (s, 1H), m/z 458 (M+H)⁺.

Example 612-chloro-N-(4-(trifluoromethyl)phenyl)-5-methylpyrimidin-4-amine(Intermediate 29)

A suspension of 2-chloro-5-methylpyrimidin-4-amine (159 μL, 1.2 mmol),1-bromo-4-(trifluoromethyl)benzene (150 mg, 1.0 mmol), potassiumtert-butoxide (224 mg, 2.0 mmol), Xantphos (120 mg, 0.2 mmol), andpalladium acetate (26 mg, 0.1 mmol) was sealed in a microwave reactiontube and irradiated at 160° C. for 15 min. The mixture was allowed tocool to room temperature, the solids were filtered using DCM to rinse,and the solution was concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (hexane to EtOAc) toafford the title intermediate 29 (128.7 mg, 43%) as a white solid. MS(ESI+): m/z 288 (M+H)⁺.

Example 62N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(4-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine(Compound XXXV)

A mixture of the above-described intermediates 29 (128 mg, 0.5 mmol) and6 (212 mg, 1.0 mmol) were suspended in acetic acid (5 mL) and heated at75° C. for 18 h. The mixture was allowed to cool to room temperature andacetic acid removed under reduced pressure. The residue was basifiedwith sat., aq NaHCO₃ (50 mL) and extracted with DCM (2×50 mL). Theorganic layer was concentrated in vacuo and the crude product purifiedby reverse phase flash chromatography on C18 (water to CH₃CN, 0.1% TFA).The aqueous fractions were neutralized with sat, aq NaHCO₃ and extractedwith EtOAc. The organics were concentrated in vacuo and the residuetaken up in DCM. HCl in dioxane was added along with ether and theresulting solid filtered to afford the hydrochloride salt of the titlecompound XXXV (166 mg, 70%) as a grey solid. ¹H NMR (500 MHz, DMSO-d₆):1.80-1.95 (m, 2H), 1.95-2.10 (m, 2H), 2.19 (s, 3H), 3.05-3.20 (m, 2H),3.55-3.65 (m, 6H), 4.33 (t, J=4.7 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 7.34(d, J=8.8 Hz, 2H), 7.73 (d, J=8.5 Hz, 2H), 7.83 (d, J=8.0 Hz, 2H), 7.94(s, 1H), 9.92 (br s, 1H), 10.44 (br s, 1H), 10.85 (br s, 1H); MS (ESI+):m/z 458.5 (M+H)⁺.

Example 63Benzo[1,3]dioxol-4-yl-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 30)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.4 g, 9.7 mmol),4-bromo-benzo[1,3]dioxole (2.0 g, 10 mmol), Pd₂(dba)₃ (0.80 g, 0.87mmol), Xantphos (1.0 g, 1.7 mmol) and cesium carbonate (6.3 g, 19 mmol)was suspended in dioxane (40 mL) and heated at reflux under the argonatmosphere for 5 h. The reaction mixture was cooled to room temperatureand diluted with DCM (30 mL). The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (hexanes to 50% EtOAc/hexanes) to afford the titlecompound (1.0 g, 39%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ2.13 (s, 3H), 5.99 (s, 2H), 6.80-6.90 (m, 3H), 8.01 (s, 1H), 8.92 (s,1H). MS (ES+): m/z 264 (M+H)⁺.

Example 64N⁴-Benzo[1,3]dioxol-4-yl-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound XXXVI)

A mixture of intermediate 30 (0.25 g, 0.95 mmol) and4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.40 g, 1.9 mmol) in aceticacid (15 mL) was heated at 100° C. for 20 h. The mixture was allowed tocool to room temperature and acetic acid removed under reduced pressure.The residue was taken in water (20 mL) and neutralized to pH˜7 with 10%NaOH solution. The resulting solution was extracted with EtOAc (2×30 mL)and the organic layer separated. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the crude product purified by flashchromatography on silica gel (DCM to 20% MeOH/DCM) to afford the titlecompound (0.14 g, 34%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.75 (m, 4H), 2.06 (s, 3H), 2.55-2.65(m, 4H), 2.78-2.88 (m, 2H), 3.98 (t, J=5.8 Hz, 2H), 5.89 (s, 2H), 6.65(d, J=9.0 Hz, 2H), 6.79-6.84 (m, 2H), 6.89 (dd, J=7.7, 1.7 Hz, 1H), 7.45(d, J=9.1 Hz, 2H), 7.81 (s, 1H), 8.23 (s, 1H), 8.73 (s, 1H). MS (ES+):m/z 434 (M+H)⁺.

Example 65N⁴-Benzo[1,3]dioxol-4-yl-5-methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Compound XXXVII)

A mixture of intermediate 30 (0.10 g, 0.38 mmol) and4-(4-methyl-piperazin-1-yl)-phenylamine (0.12 g, 0.51 mmol) in aceticacid (3 mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 150° C. for 15 min. After cooling to room temperature, thecap was removed and the mixture concentrated. The residue was taken inwater (20 mL) and the mixture was neutralized with 10% NaOH solutionuntil solid precipitated. The solid was filtered and then purified byflash chromatography on silica gel (DCM to 15% MeOH/DCM) to afford thetitle compound (22 mg, 14%) as a light red solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.06 (s, 3H), 2.21 (s, 3H), 2.44 (t, J=4.8Hz, 4H), 2.97 (t, J=4.9 Hz, 4H), 5.89 (s, 2H), 6.67 (d, J=9.1 Hz, 2H),6.80-6.86 (m, 2H), 6.91 (dd, J=7.6, 1.7 Hz, 1H), 7.41 (d, J=9.0 Hz, 2H),7.79 (s, 1H), 8.17 (s, 1H), 8.63 (s, 1H). MS (ES+): m/z 419 (M+H)⁺.

Example 66(4-Chloro-3-methoxy-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 31)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol),4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd₂(dba)₃ (0.17g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g,7.1 mmol) was suspended in dioxane (20 mL) and heated at reflux underthe argon atmosphere for 5 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel (hexanes to 40% EtOAc/hexanes) to affordthe title compound (0.55 g, 55%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.18 (s, 3H), 3.85 (s, 3H), 7.35 (dd,J=8.6, 2.3 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 8.09(d, J=0.9 Hz, 1H), 8.91 (s, 1H). MS (ES+): m/z 284 (M+H)⁺.

Example 67N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-pyrazol-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound XXXVIII)

A suspension of intermediate 31 (0.20 g, 0.70 mmol),4-pyrazol-1-ylmethyl-phenylamine (0.14 g, 0.81 mmol), Pd₂(dba)₃ (40 mg,0.044 mmol), Xantphos (50 mg, 0.086 mmol) and cesium carbonate (0.50 g,1.5 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reactiontube and irradiated with microwave at 160° C. for 20 min. After coolingto room temperature, the cap was removed and the resulting mixturefiltered and the filtered solid washed with DCM. The filtrate wasconcentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (40 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the resulting solid wasdissolved in minimum amount of EtOAc and hexanes added until solidprecipitated. After filtration, the title compound was obtained as anoff white solid (0.13 g, 44%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 3.74 (s, 3H), 5.22 (s, 2H),6.25 (t, J=2.1 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 7.27 (d, J=9.3 Hz, 1H),7.40-7.45 (m, 3H), 7.60 (d, J=8.6 Hz, 2H), 7.75 (d, J=1.8 Hz, 1H), 7.91(s, 1H), 8.36 (s, 1H), 9.04 (s, 1H) MS (ES+): m/z 421 (M+H)⁺.

Example 685-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Intermediate 32)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.0 g, 6.9 mmol) and4-(4-methyl-piperazin-1-yl)-phenylamine (1.5 mL, 7.8 mmol) in aceticacid (15 mL) was heated at 100° C. for 2.5 h. The mixture was allowed tocool to room temperature and acetic acid removed under reduced pressure.The residue was taken in water (20 mL) and the mixture was neutralizedwith 10% NaOH solution until solid precipitated. After filtration andwashed with water, the title compound was obtained as a grey solid (1.3g, 63%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.88 (s, 3H), 2.21 (s, 3H), 2.21 (s, 3H),2.44 (t, J=4.8 Hz, 4H), 3.00 (t, J=4.8 Hz, 4H), 6.27 (s, 2H), 6.79 (d,J=9.0 Hz, 2H), 7.57 (d, J=9.0 Hz, 2H), 7.63 (s, 1H), 8.42 (s, 1H). MS(ES+): m/z 299 (M+H)⁺.

Example 69N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Compound XXXIX)

A suspension of intermediate 32 (0.30 g, 1.0 mmol),4-bromo-1-chloro-2-methoxy-benzene (0.20 mL, 1.5 mmol), Pd₂(dba)₃ (50mg, 0.055 mmol), Xantphos (65 mg, 0.11 mmol) and cesium carbonate (0.70g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (40 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/5, 30 mL). After filtration, the titlecompound was obtained as an off white solid (0.20 g, 46%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.09 (s, 3H), 2.21 (s, 3H), 2.45 (t, J=4.9Hz, 4H), 3.02 (t, J=4.9 Hz, 4H), 3.73 (s, 3H), 6.79 (d, J=9.1 Hz, 2H),7.27 (d, J=8.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.49 (d, J=2.3 Hz, 1H), 7.86(s, 1H), 8.28 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z 439 (M+H)⁺.

Example 70N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine(Compound XL)

A mixture of intermediate 31 (0.10 g, 0.35 mmol) and4-morpholin-4-yl-phenylamine (80 mg, 0.45 mmol) in acetic acid (3 mL)was sealed in a microwave reaction tube and irradiated with microwave at160° C. for 20 min. After cooling to room temperature, the cap wasremoved and the mixture concentrated. The residue was taken in water (20mL) and the mixture was neutralized with 10% NaOH solution until solidprecipitated. The solid was filtered and then purified by flashchromatography on silica gel (DCM to 10% MeOH/DCM) to afford the titlecompound (55 mg, 37%) as a light brown solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.10 (s, 3H), 3.00 (t, J=4.8 Hz, 4H),3.71-3.76 (m, 7H), 6.80 (d, J=9.0 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 7.45(dd, J=8.7, 2.2 Hz, 1H), 7.47-7.50 (m, 3H), 7.87 (s, 1H), 8.29 (s, 1H),8.75 (s, 1H). MS (ES+): m/z 426 (M+H)⁺.

Example 71N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-pyrazol-1-yl-phenyl)-pyrimidine-2,4-diamine(Compound XLI)

A mixture of intermediate 31 (90 mg, 0.32 mmol) and4-pyrazol-1-yl-phenylamine (70 mg, 0.44 mmol) in acetic acid (3 mL) wassealed in a microwave reaction tube and irradiated with microwave at160° C. for 20 min. After cooling to room temperature, the cap wasremoved and the mixture concentrated. The residue was taken in water (20mL) and the mixture neutralized with 10% NaOH solution until solidprecipitated. The solid was filtered and then purified by HPLC. Thecorrected fractions were combined and concentrated to afford the titlecompound (40 mg of TFA salt, 24%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 3.75 (s, 3H), 6.54 (t, J=1.9Hz, 1H), 7.30 (d, J=6.6 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 7.40 (d, J=8.6Hz, 1H), 7.59 (d, J=8.9 Hz, 2H), 7.71 (d, J=8.9 Hz, 2H), 7.73 (d, J=1.6Hz, 1H), 7.93 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 9.41 (s, 1H), 10.05 (s,1H). MS (ES+): m/z 407 (M+H)⁺.

Example 72N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-piperidin-1-yl-phenyl)-pyrimidine-2,4-diamine(XLII)

A mixture of intermediate 31 (0.11 g, 0.39 mmol) and4-piperidin-1-yl-phenylamine (90 mg, 0.51 mmol) in acetic acid (3 mL)was sealed in a microwave reaction tube and irradiated with microwave at160° C. for 20 min. After cooling to room temperature, the cap wasremoved and the mixture concentrated. The residue was taken in water (20mL) and the mixture neutralized with 10% NaOH solution until solidprecipitated. The solid was filtered and then purified by flashchromatography on silica gel (hexanes to 70% EtOAc/hexanes)to afford thetitle compound (10 mg, 6%) as a light brown solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.48-1.53 (m, 2H), 1.59-1.65 (m, 4H), 2.09(s, 3H), 3.00 (t, J=5.4 Hz, 4H), 3.73 (s, 3H), 6.78 (d, J=9.0 Hz, 2H),7.27 (d, J=8.7 Hz, 1H), 7.40-7.47 (m, 3H), 7.50 (d, J=2.2 Hz, 1H), 7.86(s, 1H), 8.28 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 424 (M+H)⁺.

Example 73N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-pyrimidine-2,4-diamine(XLIII)

A suspension of intermediate 31 (50 mg, 0.18 mmol),4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (50 mg, 0.24 mmol),Pd₂(dba)₃ (10 mg, 0.011 mmol), Xantphos (13 mg, 0.022 mmol) and cesiumcarbonate (0.12 g, 0.37 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 15min. After cooling to room temperature, the cap was removed and theresulting mixture filtered and the filtered solid washed with DCM. Thefiltrate was concentrated and the residue purified by flashchromatography on silica gel (DCM to 10% MeOH/DCM)to afford the titlecompound (35 mg, 44%) as an off white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.15 (s, 3H), 2.20-2.45 (m,8H), 3.35 (s, 2H), 3.75 (s, 3H), 7.07 (d, J=8.5 Hz, 2H), 7.28 (d, J=8.5Hz, 1H), 7.44 (dd, J=8.7, 2.3 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.57 (d,J=8.5 Hz, 2H), 7.91 (s, 1H), 8.36 (s, 1H), 8.98 (s, 1H). MS (ES+): m/z453 (M+H)⁺.

Example 74N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-piperazin-1-yl-phenyl)-pyrimidine-2,4-diamine(Compound XLIV)

A mixture of intermediate 31 (0.20 g, 0.70 mmol) and4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.22g, 0.79 mmol) in acetic acid (4 mL) was sealed in a microwave reactiontube and irradiated with microwave at 150° C. for 15 min. After coolingto room temperature, the cap was removed and the mixture concentrated.The residue was purified by HPLC and the corrected fractions combinedand poured into saturated NaHCO₃ solution (40 mL). The combined aqueouslayers were extracted with EtOAc (2×30 mL) and the combined organiclayers washed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and the resulting solid dissolved in minimumamount of EtOAc and hexanes added until solid precipitated. Afterfiltration, the title compound was obtained as an off white solid (0.10g, 33%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.10 (s, 3H), 3.16 (s, 8H), 3.73 (s, 3H),6.83 (d, J=9.0 Hz, 2H), 7.29 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.7, 2.1 Hz,1H), 7.49-7.52 (m, 3H), 7.88 (s, 1H), 8.32 (s, 1H), 8.81 (s, 1H) MS(ES+): m/z 425 (M+H)⁺.

Example 75N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound XLV)

A suspension of intermediate 32 (0.30 g, 1.0 mmol),3-bromo-N-tert-butyl-benzenesulfonamide (0.35 g, 1.2 mmol), Pd₂(dba)₃(60 mg, 0.066 mmol), Xantphos (70 mg, 0.12 mmol) and cesium carbonate(0.70 g, 2.1 mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (40 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/7, 40 mL). After filtration, the titlecompound was obtained as an off white solid (0.30 g, 59%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.11 (s, 3H), 2.22 (s, 3H),2.45 (t, J=4.7 Hz, 4H), 3.02 (t, J=4.8 Hz, 4H), 6.81 (d, J=9.1 Hz, 2H),7.45-7.52 (m, 4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.16 (m, 2H), 8.51(s, 1H), 8.70 (s, 1H) MS (ES+): m/z 510 (M+H)⁺.

Example 76N-tert-Butyl-3-(2-chloro-5-methyl-pyrimidin-4-ylamino)-benzenesulfonamide(Intermediate 33)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.4 g, 2.8 mmol),3-bromo-N-tert-butyl-benzenesulfonamide (1.0 g, 3.4 mmol), Pd₂(dba)₃(0.17 g, 0.19 mmol), Xantphos (0.2 g, 3.5 mmol) and cesium^(carbonate)(2.0 g, 6.1 mmol) was suspended in dioxane (25 mL) and heated at refluxunder the argon atmosphere for 3 h. The reaction mixture was cooled toroom temperature and diluted with DCM (30 mL). The mixture was filteredand the filtrate concentrated in vacuo. The residue was dissolved inEtOAc and hexanes added until solid precipitated. After filtration, thetitle compound (1.2 g, 98%) was obtained as a light brown solid. It wasused in the next step without purification. MS (ES+): m/z 355 (M+H)⁺.

Example 77N-tert-Butyl-3-[5-methyl-2-(4-morpholin-4-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound XLVI)

A mixture of intermediate 33 (0.50 g, 1.4 mmol),4-morpholin-4-ylmethyl-phenylamine (0.35 g, 1.8 mmol), Pd₂(dba)₃ (0.10g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (1.0 g,3.1 mmol) was suspended in dioxane (25 mL) and heated at reflux underthe argon atmosphere for 3 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by HPLC andthe corrected fractions combined and poured into saturated NaHCO₃solution (50 mL). The combined aqueous layers were extracted with EtOAc(2×50 mL) and the combined organic layers washed with brine, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated and theresulting solid dissolved in minimum amount of EtOAc and hexanes addeduntil solid precipitated. After filtration, the title compound wasobtained as an off white solid (0.23 g, 31%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.28-2.34 (m,4H), 3.35 (s, 2H), 3.55 (t, J=4.8 Hz, 4H), 7.10 (d, J=8.5 Hz, 2H),7.45-7.52 (m, 2H), 7.57 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.94 (s, 1H),8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.95 (s, 1H). MS (ES+):m/z 511 (M+H)⁺.

Example 78N-tert-Butyl-3-{5-methyl-2-[4-(4-oxy-morpholin-4-ylmethyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound XLVII)

A solution of the above-described compound XLVI (30 mg, 0.06 mmol) and3-chloroperbenzoic acid (77%, 14 mg, 0.06 mmol) in chloroform (30 mL)was stirred at room temperature for 1 hour. The solvent was removed byrotovap and the resulting mixture was purified by silica gel with 20%CH₃OH/CHCl₃ as an eluent to afford the title compound as an off-whitesolid (15 mg, 48%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.14 (s, 3H), 2.71 (d, J=10.9Hz, 2H), 3.63 (d, J=9.9 Hz, 2H), 4.08 (t, J=11.6 Hz, 2H), 4.28 (s, 2H),7.38 (d, J=8.5 Hz, 2H), 7.50 (d, J=5.0 Hz, 2H), 7.61 (s, 1H), 7.66 (d,J=8.5 Hz, 2H), 7.96 (s, 1H), 8.13 (m, 2H), 8.63 (s, 1H), 9.13 (s, 1H).MS (ES+): m/z 527 (M+H)⁺.

Example 79N-tert-Butyl-3-[5-methyl-2-(4-pyrazol-1-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound XLVIII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and4-pyrazol-1-yl-phenylamine (50 mg, 0.31 mmol) in acetic acid (3 mL) wassealed in a microwave reaction tube and irradiated with microwave at130° C. for 15 min. After cooling to room temperature, the cap wasremoved and the mixture concentrated. The residue was taken up in water(20 mL) and neutralized with 10% NaOH solution until solid precipitated.The brown solid was filtered and then purified by HPLC. The correctedfractions were combined and poured into saturated NaHCO₃ solution (30mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) andthe combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and the resultingsolid dissolved in minimum amount of EtOAc and hexanes added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (15 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.15 (s, 3H), 6.49 (t, J=2.2Hz, 1H), 7.50-7.55 (m, 2H), 7.58 (s, 1H), 7.62 (d, J=9.1 Hz, 2H), 7.68(d, J=1.3 Hz, 1H), 7.77 (d, J=9.1 Hz, 2H), 7.96 (s, 1H), 8.11 (s, 1H),8.13-8.16 (m, 1H), 8.33 (d, J=2.5 Hz, 1H), 8.64 (s, 1H), 9.17 (s, 1H).MS (ES+): m/z 478 (M+H)⁺.

Example 80N-tert-Butyl-3-[5-methyl-2-(6-piperazin-1-yl-pyridin-3-ylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound XLIX)

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester(90 mg, 0.32 mmol) in acetic acid (3 mL) was sealed in a microwavereaction tube and irradiated with microwave at 130° C. for 15 min. Aftercooling to room temperature, the cap was removed and the mixtureconcentrated. The residue was dissolved in DCM (5 mL) and 30% TFA/DCM (6mL) added. The mixture was stirred at room temperature for 1 h,concentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and the resulting soliddissolved in minimum amount of EtOAc and hexanes added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (10 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.11 (s, 3H), 2.83 (t, J=5.0Hz, 4H), 3.28-3.33 (m, 4H), 6.73 (d, J=9.1 Hz, 1H), 7.40-7.49 (m, 2H),7.57 (s, 1H), 7.86 (dd, J=9.1, 2.7 Hz, 1H), 7.88 (s, 1H), 8.10-8.16 (m,2H), 8.28 (d, J=2.5 Hz, 1H), 8.53 (s, 1H), 8.72 (s, 1H). MS (ES+): m/z497 (M+H)⁺.

Example 81N-tert-Butyl-3-[5-methyl-2-(4-pyrazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound L)

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and4-pyrazol-1-ylmethyl-phenylamine (50 mg, 0.29 mmol) in acetic acid (3mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 130° C. for 15 min. After cooling to room temperature, thecap was removed and the mixture concentrated. The residue was purifiedby HPLC and the corrected fractions combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthe resulting solid dissolved in minimum amount of EtOAc and hexanesadded until solid precipitated. After filtration, the title compound wasobtained as a white solid (12 mg, 9%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 5.21 (s, 2H),6.24 (t, J=1.9 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.27-7.50 (m, 3H), 7.56(s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.94 (s, 1H),8.14 (d, J=7.9 Hz, 1H), 8.59 (s, 1H), 9.01 (s, 1H). MS (ES+): m/z 492(M+H)⁺.

Example 825-Methyl-N²-[3-(piperidine-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine(Intermediate 34)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol)and 3-(piperidine-1-sulfonyl)-phenylamine (0.50 g, 2.1 mmol) in aceticacid (4 mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 130° C. for 15 min. After cooling to room temperature, thecap was removed and the mixture concentrated. The residue was taken inwater (20 mL) and pH adjusted to ˜9 with 10% NaOH solution. Theresulting solution was extracted with EtOAc (2×30 mL) and the organiclayer separated. The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo and the crude product (˜0.6 g) used in the next step withoutpurification. MS (ES+): m/z 348 (M+H)⁺.

Example 83N-tert-Butyl-3-{5-methyl-2-[3-(piperidine-1-sulfonyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LI)

A suspension of intermediate 34 (0.10 g, 0.29 mmol),3-bromo-N-tert-butyl-benzenesulfonamide (84 mg, 0.29 mmol), Pd₂(dba)₃(15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate(0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 15 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue dissolved inminimum amount of EtOAc and hexanes added until solid precipitated.After filtration, the title compound was obtained as a white solid (20mg, 12%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 1.30-1.40 (m, 2H), 1.50-1.56(m, 4H), 2.16 (s, 3H), 2.88 (t, J=5.3 Hz, 4H), 7.17 (d, J=7.8 Hz, 1H),7.43 (t, J=8.0 Hz, 1H), 7.59-7.60 (m, 2H), 7.58 (s, 1H), 8.13 (s, 1H),7.16 (dd, J=7.9, 1.9 Hz, 1H), 8.18-8.22 (m, 1H), 8.67 (s, 1H), 9.37 (s,1H). MS (ES+): m/z 559 (M+H)⁺.

Example 84N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-ylmethyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LII)

A suspension of intermediate 33 (0.10 g, 0.28 mmol),4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (65 mg, 0.32 mmol),Pd₂(dba)₃ (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesiumcarbonate (0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 170° C. for 15min. After cooling to room temperature, the cap was removed and theresulting mixture filtered and the filtered solid washed with DCM. Thefiltrate was concentrated and the residue purified by HPLC. Thefractions were combined and poured into saturated NaHCO₃ solution (30mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) andthe combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and the residuedissolved in minimum amount of EtOAc and hexanes added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (53 mg, 36%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.15 (s, 3H),2.20-2.45 (m, 4H), 3.25-3.40 (m, 6H), 7.08 (d, J=8.6 Hz, 2H), 7.45-7.52(m, 2H), 7.56 (s, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.94 (s, 1H), 8.09 (s,1H), 8.13-8.16 (m, 1H), 8.58 (s, 1H), 8.94 (s, 1H). MS (ES+): m/z 524(M+H)⁺.

Example 85N-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-yl-3-trifluoromethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound LIII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(4-amino-2-trifluoromethyl-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (0.1 g, 0.29 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol),Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.18 g, 0.55 mmol) indioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tube andirradiated with microwave at 170° C. for 15 min. After cooling to roomtemperature, the cap was removed and the resulting mixture filtered. Thefiltered solid was washed with DCM and the filtrate concentrated. Theresidue was dissolved in DCM (5 mL) and 50% TFA/DCM (6 mL) added. Themixture was stirred at room temperature for 2 h, concentrated and theresidue purified by HPLC. The corrected fractions were combined andpoured into saturated NaHCO₃ solution (30 mL). The combined aqueouslayers were extracted with EtOAc (2×30 mL) and the combined organiclayers washed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and the resulting solid dissolved in minimumamount of EtOAc and hexanes added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (42 mg,26%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.14 (s, 3H), 2.70-2.75 (m,4H), 2.80-2.85 (m, 4H), 7.36 (d, J=8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55(s, 1H), 7.90-8.00 (m, 3H), 8.07 (s, 1H), 8.15 (d, J=7.6 Hz, 1H), 8.63(s, 1H), 9.22 (s, 1H) MS (ES+): m/z 564 (M+H)⁺.

Example 863-{2-[4-(4-Acetyl-piperazin-1-yl)-3-trifluoromethyl-phenylamino]-5-methyl-pyrimidin-4-ylamino}-N-tert-butyl-benzenesulfonamide(Compound LIV)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),1-[4-(4-amino-2-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (0.1 g,0.35 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol)and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) wassealed in a microwave reaction tube and irradiated with microwave at160° C. for 15 min. After cooling to room temperature, the cap wasremoved and the resulting mixture filtered. The filtered solid waswashed with DCM and the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthe resulting solid dissolved in minimum amount of EtOAc and hexanesadded until solid precipitated. After filtration, the title compound wasobtained as a white solid (64 mg, 38%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.04 (3, H), 2.14 (s, 3H),2.73 (t, J=4.9 Hz, 2H), 2.79 (t, J=4.7 Hz, 2H), 3.50-3.60 (m, 4H), 7.40(d, J=8.7 Hz, 2H), 7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.90-8.00 (m, 3H),8.07 (s, 1H), 8.14 (d, J=7.2 Hz, 1H), 8.64 (s, 1H), 9.26 (s, 1H). MS(ES+): m/z 606 (M+H)⁺.

Example 875-Methyl-N²-[3-(4-methyl-piperazine-1-sulfonyl)-phenyl]-pyrimidine-2,4-diamine(Intermediate 35)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.25 g, 1.74 mmol)and 3-(4-methyl-piperazine-1-sulfonyl)-phenylamine (0.50 g, 2.0 mmol) inacetic acid (4 mL) was sealed in a microwave reaction tube andirradiated with microwave at 130° C. for 15 min. After cooling to roomtemperature, the cap was removed and the mixture concentrated. Theresidue was taken in water (20 mL) and pH adjusted to ˜9 with 10% NaOHsolution. The resulting solution was extracted with EtOAc (2×30 mL) andthe organic layer separated. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo and the crude product (˜0.42 g) used in the nextstep without purification. MS (ES+): m/z 363 (M+H)⁺.

Example 88N-tert-Butyl-3-{5-methyl-2-[3-(4-methyl-piperazine-1-sulfonyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LV)

A suspension of intermediate 35 (0.10 g, 0.28 mmol),3-bromo-N-tert-butyl-benzenesulfonamide (80 mg, 0.27 mmol), Pd₂(dba)₃(15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol) and cesium carbonate(0.18 g, 0.55 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 15 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue dissolved inminimum amount of EtOAc and hexanes added until solid precipitated.After filtration, the title compound was obtained as a white solid (10mg, 6%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.16 (s, 3H),2.33-2.40 (m, 4H), 2.85-2.94 (m, 4H), 7.18 (d, J=8.1 Hz, 1H), 7.44 (t,J=8.0 Hz, 1H), 7.49-7.54 (m, 2H), 7.58 (s, 1H), 8.00-8.03 (m, 2H), 8.13(s, 1H), 8.15 (dd, J=8.6, 1.6 Hz, 1H), 8.18-8.23 (m, 1H), 8.66 (s, 1H),9.38 (s, 1H). MS (ES+): m/z 574 (M+H)⁺.

Example 89N-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound LVI)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g,0.34 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Xantphos (20 mg, 0.035 mmol)and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) wassealed in a microwave reaction tube and irradiated with microwave at170° C. for 15 min. After cooling to room temperature, the cap wasremoved and the resulting mixture filtered. The filtered solid waswashed with DCM and the filtrate concentrated. The residue was dissolvedin DCM (6 mL) and TFA (3 mL) added. The mixture was stirred at roomtemperature for 1 h, concentrated and the residue purified by HPLC. Thecorrected fractions were combined and poured into saturated NaHCO₃solution (30 mL). The combined aqueous layers were extracted with EtOAc(2×30 mL) and the combined organic layers washed with brine, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated and theresulting solid triturated in hexanes/EtOAc (10/1, 55 mL). Afterfiltration, the title compound was obtained as a white solid (32 mg,22%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.30-2.40 (m,4H), 2.85 (t, J=4.7 Hz, 4H), 3.38 (s, 2H), 7.09 (d, J=8.5 Hz, 2H),7.45-7.52 (m, 2H), 7.56 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.94 (s, 1H),8.10 (s, 1H), 8.13-8.16 (m, 1H), 8.59 (s, 1H), 8.96 (s, 1H). MS (ES+):m/z 510 (M+H)⁺.

Example 90N-tert-Butyl-3-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LVII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol) and4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.10 g, 0.49 mmol) in aceticacid (3 mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 150° C. for 20 min. After cooling to room temperature, thecap was removed and the mixture concentrated. The residue was purifiedby HPLC and the corrected fractions combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthe resulting solid dissolved in minimum amount of EtOAc and hexanesadded until solid precipitated. After filtration, the title compound wasobtained as a white solid (40 mg, 27%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 1.65-1.70 (m, 4H), 2.12 (s,3H), 2.45-2.55 (m, 4H), 2.76 (t, J=5.8 Hz, 2H), 3.99 (t, J=6.0 Hz, 2H),6.79 (d, J=9.0 Hz, 2H), 7.46-7.53 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H),8.10-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 525 (M+H)⁺.

Example 913-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LVIII)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd₂(dba)₃ (20 mg, 0.022mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77mmol) in dioxane (3 mL) was sealed in a microwave reaction tube andirradiated with microwave at 160° C. for 15 min. After cooling to roomtemperature, the cap was removed and the resulting mixture filtered andthe filtered solid washed with DCM. The filtrate was concentrated andthe residue purified by HPLC. The fractions were combined and pouredinto saturated NaHCO₃ solution (30 mL). The combined aqueous layers wereextracted with EtOAc (2×30 mL) and the combined organic layers washedwith brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated to afford the title compound as a grey solid (10 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.10 (s, 3H), 2.22 (s, 3H), 2.44 (t, J=4.9Hz, 4H), 3.03 (t, J=4.9 Hz, 4H), 6.81 (d, J=9.0 Hz, 2H), 7.34 (s, 2H),7.45-7.50 (m, 4H), 7.89 (s, 1H), 8.06 (s, 1H), 8.13-8.18 (m, 1H), 8.54(s, 1H), 8.70 (s, 1H). MS (ES+): m/z 454 (M+H)⁺.

Example 92N-Methyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LIX)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-N-methyl-benzenesulfonamide (0.11 g, 0.44 mmol), Pd₂(dba)₃ (20mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of DCM/Et₂O (1/5, 30 mL). After filtration, the title compoundwas obtained as a light brown solid (65 mg, 42%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.23 (s, 3H), 2.44 (d, J=5.0Hz, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J=4.9 Hz, 4H), 6.81 (d, J=9.1 Hz,2H), 7.40-7.43 (m, 2H), 7.46 (d, J=9.1 Hz, 2H), 7.52 (t, J=8.0 Hz, 1H),7.89 (s, 1H), 7.94 (t, J=1.8 Hz, 1H), 8.29 (br d, J=8.3 Hz, 1H), 8.56(s, 1H), 8.72 (s, 1H). MS (ES+): m/z 468 (M+H)⁺.

Example 93N,N-Dimethyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LX)

A suspension of intermediate 32 (0.13 g, 0.43 mmol),3-bromo-N,N-dimethyl-benzenesulfonamide (0.14 g, 0.53 mmol), Pd₂(dba)₃(25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate(0.33 g, 1.0 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/5, 30 mL). After filtration, the titlecompound was obtained as an off white solid (60 mg, 29%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 2.23 (s, 3H), 2.44 (d, J=5.0Hz, 3H), 2.45-2.50 (m, 4H), 2.63 (s, 6H), 3.03 (t, J=4.9 Hz, 4H), 6.81(d, J=9.1 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.45 (d, J=9.1 Hz, 2H), 7.54(t, J=8.0 Hz, 1H), 7.84 (t, J=1.9 Hz, 1H), 7.90 (s, 1H), 8.46 (br d,J=7.8 Hz, 1H), 8.57 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 482 (M+H)⁺.

Example 94N-Isopropyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LXI)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-N-isopropyl-benzenesulfonamide (0.11 g, 0.39 mmol), Pd₂(dba)₃(20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate(0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/10, 33 mL). After filtration, the titlecompound was obtained as an off white solid (47 mg, 29%).

¹H NMR (500 MHz, DMSO-d₆): δ 0.98 (d, J=6.6 Hz, 6H), 2.11 (s, 3H), 2.24(s, 3H), 2.45-2.50 (m, 4H), 3.03 (t, J=4.8 Hz, 4H), 3.20-3.27 (m, 1H),6.80 (d, J=9.0 Hz, 2H), 7.40-7.52 (m, 4H), 7.59 (d, J=7.1 Hz, 1H), 7.89(s, 1H), 8.21 (br d, J=7.9 Hz, 1H), 8.53 (s, 1H), 8.71 (s, 1H). MS(ES+): m/z 496 (M+H)⁺.

Example 95N⁴-(3-Methanesulfonyl-4-methyl-phenyl)-5-methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Compound LXII)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),4-bromo-2-methanesulfonyl-1-methyl-benzene (0.10 g, 0.40 mmol),Pd₂(dba)₃ (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesiumcarbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 15min. After cooling to room temperature, the cap was removed and theresulting mixture filtered and the filtered solid washed with DCM. Thefiltrate was concentrated and the residue purified by HPLC. Thefractions were combined and poured into saturated NaHCO₃ solution (30mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) andthe combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and the residuetriturated in a mixture of EtOAc/hexanes (1/5, 30 mL). After filtration,the title compound was obtained as a light brown solid (41 mg, 27%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.09 (s, 3H), 2.22 (s, 3H), 2.45 (t, J=4.7Hz, 4H), 2.61 (s, 3H), 3.03 (t, J=4.9 Hz, 4H), 3.20 (s, 3H), 6.80 (d,J=9.1 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.87 (s,1H), 8.05 (d, J=2.4 Hz, 1H), 8.21 (br d, J=7.0 Hz, 1H), 8.55 (s, 1H),8.71 (s, 1H). MS (ES+): m/z 467 (M+H)⁺.

Example 96N-Cyclohexyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LXIII)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-N-cyclohexyl-benzenesulfonamide (0.13 g, 0.41 mmol), Pd₂(dba)₃(20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate(0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 15 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/10, 33 mL). After filtration, the titlecompound was obtained as an off white solid (45 mg, 25%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.07-1.17 (m, 6H), 1.53-1.63 (m, 4H), 2.11(s, 3H), 2.22 (s, 3H), 2.45 (t, J=4.7 Hz, 4H), 2.90-3.00 (m, 1H), 3.02(t, J=4.8 Hz, 4H), 6.80 (d, J=9.1 Hz, 2H), 7.43-7.53 (m, 4H), 7.65 (d,J=7.3 Hz, 1H), 7.89 (s, 1H), 8.05 (s, 1H), 8.18 (br d, J=7.7 Hz, 1H),8.52 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 536 (M+H)⁺.

Example 97N,N-Diethyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LXIV)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-N,N-diethyl-benzenesulfonamide (0.12 g, 0.41 mmol), Pd₂(dba)₃(20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate(0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 15 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/10, 33 mL). After filtration, the titlecompound was obtained as an off white solid (45 mg, 27%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.06 (t, J=7.1 Hz, 6H), 2.11 (s, 3H), 2.22(s, 3H), 2.44 (t, J=4.7 Hz, 4H), 3.03 (t, J=4.8 Hz, 4H), 3.16 (q, J=7.1Hz, 4H), 6.80 (d, J=9.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 1H), 7.45 (d, J=9.0Hz, 2H), 7.50 (t, J=8.1 Hz, 1H), 7.89 (t, J=1.9 Hz, 1H), 7.89 (s, 1H),8.39 (br d, J=7.9 Hz, 1H), 8.53 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 510(M+H)⁺.

Example 985-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-[3-(morpholine-4-sulfonyl)-phenyl]-pyrimidine-2,4-diamine(Compound LXV)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),4-(3-bromo-benzenesulfonyl)-morpholine (0.12 g, 0.39 mmol), Pd₂(dba)₃(20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate(0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 15 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered and the filtered solid washed with DCM. The filtratewas concentrated and the residue purified by HPLC. The fractions werecombined and poured into saturated NaHCO₃ solution (30 mL). The combinedaqueous layers were extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/10, 33 mL). After filtration, the titlecompound was obtained as a light red solid (90 mg, 52%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.12 (s, 3H), 2.22 (s, 3H), 2.45 (t, J=4.8Hz, 4H), 2.89 (t, J=4.6 Hz, 4H), 3.03 (t, J=4.8 Hz, 4H), 3.64 (t, J=4.7Hz, 4H), 6.81 (d, J=9.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 7.45 (d, J=9.0Hz, 2H), 7.56 (t, J=8.1 Hz, 1H), 7.84 (t, J=1.9 Hz, 1H), 7.91 (s, 1H),8.47 (br d, J=8.4 Hz, 1H), 8.59 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 524(M+H)⁺.

Example 993-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzoicacid ethyl ester (Intermediate 36)

A suspension of intermediate 32 (0.10 g, 0.33 mmol), 3-bromo-benzoicacid ethyl ester (0.07 mL, 0.44 mmol), Pd₂(dba)₃ (20 mg, 0.022 mmol),Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.25 g, 0.77 mmol) indioxane (3 mL) was sealed in a microwave reaction tube and irradiatedwith microwave at 160° C. for 15 min. After cooling to room temperature,the cap was removed and the resulting mixture filtered and the filteredsolid washed with DCM. The filtrate was concentrated and the residuepurified by flash chromatography on silica gel (DCM to 10% MeOH/DCM) toafford the title compound (0.10 g, 68%). MS (ES+): m/z 447 (M+H)⁺.

Example 1003-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzamide(Compound LXVI)

A mixture of intermediate 36 (0.10 g, 0.22 mmol) in concentrated NH₄OHwas sealed in a reaction tube and heated at 50° C. for 3 d. The mixturewas poured into water (15 mL) and extracted with EtOAc (2×30 mL). Thecombined organic layers were washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and the residuepurified by HPLC. The corrected fractions were combined and poured intosaturated NaHCO₃ solution (30 mL). The aqueous layer was extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthe residue triturated in a mixture of EtOAc/hexanes (1/10, 33 mL).After filtration, the title compound was obtained as a white solid (10mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.10 (s, 3H), 2.22 (s, 3H), 2.40-2.50 (m,4H), 2.95-3.05 (m, 4H), 6.75 (d, J=9.1 Hz, 2H), 7.30-7.40 (m, 2H), 7.45(d, J=9.1 Hz, 2H), 7.53-7.58 (m, 1H), 7.85 (s, 1H), 7.90 (br s, 2H),8.03 (s, 1H), 8.37 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 418 (M+H)⁺.

Example 1012-Methyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzoicacid ethyl ester (Compound LXVII)

A suspension of intermediate 32 (0.10 g, 0.33 mmol),3-bromo-2-methyl-benzoic acid ethyl ester (0.10 mL, 0.41 mmol),Pd₂(dba)₃ (20 mg, 0.022 mmol), Xantphos (25 mg, 0.043 mmol) and cesiumcarbonate (0.25 g, 0.77 mmol) in dioxane (3 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 20min. After cooling to room temperature, the cap was removed and theresulting mixture filtered and the filtered solid washed with DCM. Thefiltrate was concentrated and the residue purified by flashchromatography on silica gel (DCM to 30% MeOH and 1% TEA in DCM) toafford the title compound (0.14 g, 92%) as a light brown oil.

¹H NMR (500 MHz, DMSO-d₆): δ 1.32 (t, J=7.1 Hz, 3H), 2.10 (s, 3H), 2.21(s, 3H), 2.32 (s, 3H), 2.40-2.45 (m, 4H), 2.94 (t, J=4.8 Hz, 4H), 4.30(q, J=7.1 Hz, 2H), 6.57 (d, J=9.1 Hz, 2H), 7.25 (d, J=8.9 Hz, 2H), 7.35(t, J=7.8 Hz, 1H), 7.48 (dd, J=7.9, 1.0 Hz, 1H), 7.70 (dd, J=7.8, 1.1Hz, 1H), 7.78 (s, 1H), 8.23 (s, 1H), 8.58 (s, 1H). MS (ES+): m/z 461(M+H)⁺.

Example 102.2-Methyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzamide(Compound LXVIII)

To a mixture of the above-described compound LXVII (0.10 g, 0.22 mmol)and formamide (0.05 mL, 1.3 mmol) in DMF (5 mL) at 100° C. was addedNaOMe (0.10 g, 0.46 mmol) under the argon atmosphere. The mixture wasstirred at the same temperature for 2 h and then at room temperature foradditional 15 h. The mixture was poured into water (15 mL) and extractedwith EtOAc (2×15 mL). The combined organic layers were washed withbrine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Theaqueous layer was extracted with EtOAc (2×30 mL) and the combinedorganic layers washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue triturated in amixture of EtOAc/hexanes (1/5, 30 mL). After filtration, the titlecompound was obtained as a white solid (20 mg, 21%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.09 (s, 3H), 2.21 (s, 3H), 2.23 (s, 3H),2.40-2.45 (m, 4H), 2.97 (t, J=4.8 Hz, 4H), 6.69 (d, J=9.1 Hz, 2H),7.24-7.28 (m, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.39-7.43 (m, 2H), 7.69 (s,1H), 7.78 (s, 1H), 8.01 (s, 1H), 8.53 (s, 1H). MS (ES+): m/z 432 (M+H)⁺.

Example 103(2-Chloro-5-methyl-pyrimidin-4-yl)-(4-chloro-3-trifluoromethyl-phenyl)-amine(Intermediate 37)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.30 g, 2.1 mmol),4-bromo-1-chloro-2-trifluoromethyl-benzene (0.40 mL, 2.7 mmol),Pd₂(dba)₃ (0.10 g, 0.11 mmol), Xantphos (0.13 g, 0.22 mmol) and cesiumcarbonate (1.5 g, 4.6 mmol) in dioxane/DMF (6/1, 7 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 15min. After cooling to room temperature, the cap was removed and theresulting mixture filtered and the filtered solid washed with DCM. Thefiltrate was concentrated and the residue purified by flashchromatography on silica gel (hexanes to 50% EtOAc/hexanes) to affordthe title compound (0.65 g, 96%) as a white solid. MS (ES+): m/z 322(M+H)⁺.

Example 104N⁴-(4-Chloro-3-trifluoromethyl-phenyl)-5-methyl-N²-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine(Compound LXIX)

A mixture of intermediate 37 (0.10 g, 0.31 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.12g, 0.41 mmol) in acetic acid (3 mL) was sealed in a microwave reactiontube and irradiated with microwave at 150° C. for 15 min. After coolingto room temperature, the cap was removed and the mixture concentrated.The residue was taken in water (20 mL) and neutralized with 10% NaOHsolution until solid precipitated. The resulting solid was filtered andpurified by HPLC. The corrected fractions were combined and poured intosaturated NaHCO₃ solution (30 mL). The aqueous layer was extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated toafford the title compound as a white solid (30 mg, 20%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.69-1.77 (m, 2H), 2.00-2.04 (m, 2H), 2.11(s, 3H), 2.90-3.00 (m, 2H), 3.10-3.20 (m, 2H), 4.40-4.48 (m, 1H), 6.84(d, J=9.0 Hz, 2H), 7.49 (d, J=9.0 Hz, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.94(s, 1H), 8.12 (d, J=2.6 Hz, 1H), 8.21 (br d, J=8.2 Hz, 1H), 8.64 (s,1H), 8.93 (s, 1H). MS (ES+): m/z 478 (M+H)⁺.

Example 1055-Methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Intermediate 38)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol)and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (1.1 g, 5.3 mmol) in aceticacid (8 mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 150° C. for 15 min. After cooling to room temperature, thecap was removed and the mixture concentrated. The residue was taken inwater (30 mL) and neutralized with 10% NaOH solution until pH˜10. Theresulting aqueous layer was extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated to afford the title compoundas a grey solid (0.80 g, 73%). It was used in the next step withoutpurification. MS (ES+): m/z 314 (M+H)⁺.

Example 1063-{5-Methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound LXX)

A mixture of intermediate 38 (0.10 g, 0.32 mmol),3-bromo-benzenesulfonamide (0.10 g, 0.42 mmol), Pd₂(dba)₃ (20 mg, 0.022mmol), Xantphos (25 mg, 0.043 mmol) and cesium carbonate (0.20 g, 0.61mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 170° C. for 25 min. After cooling toroom temperature, the cap was removed and the resulting mixture filteredand the filtered solid washed with DCM. The filtrate was concentratedand the residue purified by HPLC. The corrected fractions were combinedand poured into saturated NaHCO₃ solution (30 mL). The aqueous layer wasextracted with EtOAc (2×30 mL) and the combined organic layers washedwith brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated and solid triturated in a mixture of EtOAc/hexanes (1/10,33 mL). After filtration, the title compound was obtained as a whitesolid (11 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.49-2.52(m, 4H), 2.75-2.80 (m, 2H), 4.00 (t, J=5.9 Hz, 2H), 6.80 (d, J=9.0 Hz,2H), 7.34 (s, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J=9.0 Hz, 2H), 7.90 (s,1H), 8.05 (s, 1H), 8.10-8.15 (m, 1H), 8.57 (s, 1H), 8.77 (s, 1H). MS(ES+): m/z 469 (M+H)⁺.

Example 1075-Methyl-N²-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Intermediate 39)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.40 g, 2.8 mmol)and 4-morpholin-4-ylmethyl-phenylamine (0.60 g, 3.1 mmol) in acetic acid(15 mL) was heated at 70° C. for 17 h. After cooling to roomtemperature, the mixture was concentrated. The residue was taken inwater (30 mL) and neutralized with 10% NaOH solution until pH˜10. Theresulting aqueous layer was extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated to afford the title compoundas a brown syrup (0.70 g, 83%). It was used in the next step withoutpurification. MS (ES+): m/z 300 (M+H)⁺

Example 108N⁴-(1H-Indol-4-yl)-5-methyl-N²-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound LXXI)

A mixture of intermediate 39 (0.40 g, 1.3 mmol),4-bromo-1-triisopropylsilanyl-1H-indole (0.50 g, 1.4 mmol), Pd₂(dba)₃(0.10 g, 0.11 mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate(0.90 g, 2.8 mmol) was suspended in dioxane (20 mL) and heated at refluxunder the argon atmosphere for 4 h. The reaction mixture was cooled toroom temperature and diluted with DCM (30 mL). The mixture was filteredand the filtrate concentrated in vacuo. The residue was purified byflash chromatography on silica gel (hexanes to EtOAc) to afford the TIPSprotected precursor as a yellow oil.

To the above TIPS protected precursor (50 mg, 0.088 mmol) in THF (5 mL)was added TBAF (0.5 mL, 1M in THF). The mixture was stirred at roomtemperature for 1 h and then poured into water (20 mL). The aqueouslayer was extracted with EtOAc (2×20 mL) and the combined organic layerswashed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and the residue purified by HPLC. Thecorrected fractions were combined and poured into saturated NaHCO₃solution (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL)and the combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and solid dissolvedin minimum amount of EtOAc and then hexanes added until solidprecipitated. After filtration, the title compound was obtained as alight brown solid (6 mg, 1% overall yield).

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 2.25-2.30 (m, 4H), 3.29 (s,2H), 3.54 (t, J=4.5 Hz, 4H), 6.40 (t, J=2.2 Hz, 1H), 6.89 (d, J=8.5 Hz,2H), 7.09 (t, J=7.8 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.27 (t, J=2.8 Hz,1H), 7.30 (d, J=7.5 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.85 (s, 1H), 8.14(s, 1H), 8.77 (s, 1H), 11.10 (s, 1H). MS (ES+): m/z 415 (M+H)⁺.

Example 1094-[4-(4-Amino-5-methyl-pyrimidin-2-ylamino)-benzyl]-piperazine-1-carboxylicacid tert-butyl ester (Intermediate 40)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol)and 4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester(0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70° C. for 1 d.After cooling to room temperature, the mixture was concentrated. Theresidue was taken in water (30 mL) and neutralized with 10% NaOHsolution until pH˜10. The resulting aqueous layer was extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthe title compound used in the next step without purification. MS (ES+):m/z 399 (M+H)⁺.

Example 110N⁴-(1H-Indol-4-yl)-5-methyl-N²-(4-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound LXXII)

A mixture of intermediate 40 (0.78 g, 2.0 mmol),4-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 2.0 mmol), Pd₂(dba)₃(0.15 g, 0.16 mmol), Xantphos (0.19 g, 0.32 mmol) and cesium carbonate(1.3 g, 4.0 mmol) was suspended in dioxane (20 mL) and heated at refluxunder the argon atmosphere for 4.5 h. The reaction mixture was cooled toroom temperature, filtered and the filtered solid was with DCM (30 mL).The filtrate was concentrated and the residue purified by flashchromatography on silica gel (hexanes to 30% EtOAc/hexanes) to affordthe TIPS protected precursor.

To the above TIPS protected precursor (0.10 g, 0.15 mmol) in DCM (8 mL)was added TFA (2 mL). The mixture was stirred at room temperature for 2h and then concentrated. The residue was purified by HPLC and thecorrected fractions combined and poured into saturated NaHCO₃ solution(30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and solid triturated in amixture of EtOAc/hexanes (1/5, 30 mL). After filtration, the titlecompound was obtained as a white solid (25 mg, 3% overall yield).

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 2.20-2.30 (m, 4H), 2.73 (t,J=4.6 Hz, 4H), 3.28 (s, 2H), 6.41 (t, J=2.2 Hz, 1H), 6.89 (d, J=8.5 Hz,2H), 7.09 (t, J=7.8 Hz, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.27 (t, J=2.8 Hz,1H), 7.31 (d, J=7.5 Hz, 1H), 7.44 (d, J=8.5 Hz, 2H), 7.85 (s, 1H), 8.13(s, 1H), 8.77 (s, 1H), 11.10 (s, 1H) MS (ES+): m/z 414 (M+H)⁺.

Example 1115-Methyl-N⁴-(7-methyl-1H-indol-4-yl)-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound LXXIII)

A mixture of intermediate 32 (674 mg, 2.25 mmol),4-bromo-7-methyl-1H-indole (522 mg, 2.48 mmol), Pd₂(dba)₃ (182 mg, 0.2mmol), Xantphos (360 mg, 0.6 mmol) and cesium carbonate (2.6 g, 8 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (136 mg of HCl salt, 13%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.21 (s, 3H), 2.55 (s, 3H), 2.80 (d, J=4.6Hz, 3H), 3.00-3.05 (m, 2H), 3.10-3.16 (m, 2H), 3.45-3.48 (m, 2H),3.64-3.66 (m, 2H), 6.33-6.34 (m, 1H), 6.63 (br, 2H), 6.92-6.97 (m, 4H),7.35 (t, J=2.7 Hz, 1H), 7.83 (s, 1H), 10.04 (s, 1H), 10.24 (s, 1H),11.08 (br s, 1H), 11.34 (s, 1H), 12.12 (br s, 1H). MS (ES+): m/z 428(M+H)⁺.

Example 112N⁴-(7-Chloro-1H-indol-4-yl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound LXXIV)

A mixture of intermediate 32 (298 mg, 1.0 mmol),4-bromo-7-chloro-1H-indole (231 mg, 1.04 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (251 mg of HCl salt, 51%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.21 (s, 3H), 2.80 (d, J=4.6 Hz, 3H),3.01-3.05 (m, 2H), 3.08-3.13 (m, 2H), 3.46-3.48 (m, 2H), 3.65-3.67 (m,2H), 6.46-6.47 (m, 1H), 6.64 (br s, 1H), 6.93 (d, J=8.9 Hz, 2H), 7.05(d, J=8.1 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H), 7.43-7.44 (m, 1H), 7.87 (s,1H), 10.13 (s, 1H), 10.27 (s, 1H), 11.00 (br s, 1H), 11.70 (s, 1H),12.23 (br s, H). MS (ES+): m/z 448 (M+H)⁺.

Example 113N²-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-(7-methyl-1H-indol-4-yl)pyrimidine-2,4-diamine(Compound LXXV)

A mixture of intermediate 38 (410 mg, 1.3 mmol),4-bromo-7-methyl-1H-indole (275 mg, 1.3 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (92 mg of HCl salt, 15%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21(s, 3H), 2.55 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.26 (t,J=4.9 Hz, 2H), 6.33-6.34 (m, 1H), 6.61 (br d, 2H), 6.93-6.95 (m, 2H),7.03 (d, J=8.9 Hz, 2H), 7.34 (t, J=2.8 Hz, 1H), 7.85 (s, 1H), 10.07 (s,1H), 10.33 (s, 1H), 10.91 (br s, 1H), 11.34 (s, 1H), 12.15 (br s, H). MS(ES+): m/z 443 (M+H)⁺.

Example 114N²-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-(7-chloro-1H-indol-4-yl)pyrimidine-2,4-diamine(Compound LXXVI)

A mixture of intermediate 38 (270 mg, 0.86 mmol),4-bromo-7-chloro-1H-indole (198 mg, 0.86 mmol), Pd₂(dba)₃ (72 mg, 0.08mmol), Xantphos (140 mg, 0.24 mmol) and cesium carbonate (1.3 g, 4 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (33 mg of HCl salt, 8%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.22(s, 3H), 3.06-3.10 (m, 2H), 3.51-3.54 (m, 4H), 4.27 (t, J=4.9 Hz, 2H),6.46-6.47 (m, 1H), 6.63 (br d, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.06 (d,J=8.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.43 (t, J=2.8 Hz, 1H), 7.90 (s,1H), 10.13 (s, 1H), 10.40 (s, 1H), 10.94 (br s, 1H), 11.70 (s, 1H),12.33 (br s, H). MS (ES+): m/z 463 (M+H)⁺.

Example 115N²-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-(7-fluoro-1H-indol-4-yl)pyrimidine-2,4-diamine(Compound LXXVII)

A mixture of intermediate 38 (413 mg, 1.3 mmol),4-bromo-7-fluoro-1H-indole (310 mg, 1.45 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (10 mg of HCl salt, 1.5%) as a brown solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.88-1.90 (m, 2H), 1.93-2.02 (m, 2H), 2.21(s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m, 4H), 4.26 (t, J=4.9 Hz, 2H),6.42-6.43 (m, 1H), 6.63 (br d, 2H), 6.95-7.04 (m, 3H), 7.35 (d, J=8.9Hz, 1H), 7.42 (t, J=2.8 Hz, 1H), 7.89 (s, 1H), 10.08 (s, 1H), 10.41 (s,1H), 10.90 (br s, 1H), 11.85 (s, 1H), 12.33 (br s, H). MS (ES+): m/z 447(M+H)⁺.

Example 116N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound LXXVIII)

A mixture of intermediate 32 (298 mg, 1.0 mmol),1-tert-butyl-3-bromobenzene (256 mg, 1.2 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol)was suspended in dioxane (50 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (27 mg of HCl salt, 6%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.25 (s, 9H), 2.16 (s, 3H), 2.80 (d, J=4.6Hz, 3H), 3.04-3.16 (m, 4H), 3.47-3.49 (m, 2H), 3.65-3.67 (m, 2H), 6.90(d, J=8.9 Hz, 2H), 7.26 (d, J=9.0 Hz, 2H), 7.28-7.35 (m, 2H), 7.45 (t,J=1.8 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.86 (s, 1H), 9.70 (s, 1H), 10.37(s, 1H), 11.01 (br s, 1H), 12.34 (br s, H). MS (ES+): m/z 431 (M+H)⁺.

Example 117 N-(3-tert-Butylphenyl)-2-chloro-5-methylpyrimidin-4-amine(Intermediate 41)

A mixture of 2-chloro-5-methylpyrimidin-4-amine (670 mg, 4.7 mmol),1-tert-butyl-3-bromobenzene (1.5 g, 7 mmol), Pd₂(dba)₃ (366 mg, 0.4mmol), Xantphos (695 mg, 1.2 mmol) and cesium carbonate (6.2 g, 19 mmol)was suspended in dioxane (150 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in EtOAc (10 mL) andadded hexanes (100 mL). The solid was collected by filtration and washedwith hexanes to afford the crude title compound (1.2 g, 99%) as a yellowsolid.

Example 118N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound LXXIX)

A mixture of intermediate 41 (740 mg, 2.68 mmol) and tert-butyl4-(4-aminophenoxy)piperidine-1-carboxylate (500 mg, 1.71 mmol) wassuspended in acetic acid (10 mL) and heated at 100° C. for 4 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken in water (20 mL) andneutralized to pH˜7. The resulting solution was extracted with EtOAc (30mL) and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and the crude product purified by HPLC to afford the titlecompound (276 mg of HCl salt, 35%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.22 (s, 9H), 1.77-1.81 (m, 2H), 2.03-2.07(m, 2H), 2.14 (s, 3H), 3.00-3.04 (m, 2H), 3.18 (br s, 2H), 4.56-4.57 (m,1H), 6.86 (d, J=8.9 Hz, 2H), 7.26-7.31 (m, 4H), 7.40 (s, 1H), 7.44 (d,J=7.5 Hz, 1H), 7.84 (s, 1H), 8.93 (br s, 1H), 8.99 (br s, 1H), 9.67 (s,1H), 10.31 (s, 1H). MS (ES+): m/z 432 (M+H)⁺.

Example 119 tert-Butyl4-(4-(4-amino-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate(Intermediate 42)

A mixture of 2-chloro-5-methylpyrimidin-4-amine (540 mg, 3.7 mmol),tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (1.1 g, 3.7 mmol)was suspended in acetic acid (20 mL) and heated at 70° C. for 1 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken in water (20 mL) andneutralized to pH˜7. The resulting solution was extracted with EtOAc (30mL) and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo to afford the title compound (1.4 g, 95%) as a yellow solid.

Example 120N⁴-(1H-Indazol-4-yl)-5-methyl-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound LXXX)

A mixture of intermediate 42 (480 mg, 1.2 mmol), 4-bromo-1H-indazole(236 mg, 1.2 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3mmol) and cesium carbonate (1.3 g, 4 mmol) was suspended in dioxane (50mL) and heated at reflux under the argon atmosphere for 20 h. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by HPLC to afford the title compound (4 mg of HCl salt,1.2%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.75-1.80 (m, 2H), 2.02-2.07 (m, 2H), 2.24(s, 3H), 3.05-3.09 (m, 2H), 3.17-3.21 (m, 2H), 4.52 (br s, 1H), 6.63 (d,J=8.6 Hz, 2H), 7.01 (d, J=8.6 Hz, 2H), 7.14 (d, J=7.3 Hz, 2H), 7.38-7.44(m, 2H), 7.62 (d, J=8.9 Hz, 2H), 7.92 (s, 1H), 8.02 (s, 1H), 9.00 (br s,1H), 9.04 (br s, 1H), 10.20 (s, 1H), 10.33 (s, 1H). MS (ES+): m/z 416(M+H)⁺.

Example 1214-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino]-benzyl}-piperazine-1-carboxylicacid tert-butyl ester (Intermediate 43)

A mixture of intermediate 31 (0.092 g, 0.33 mmol),4-(3-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.11g, 0.39 mmol), Pd₂(dba)₃ (0.03 g, 0.033 mmol), Xantphos (0.038 g, 0.065mmol) and cesium carbonate (0.32 g, 0.98 mmol) was suspended in dioxane(5 mL) and microwaved at 160° C. for 15 min. The reaction mixture wascooled to room temperature and centrifuged down. The reaction wasdecanted and the organic phase concentrated in vacuo. The residue waspurified by HPLC to afford the title compound (0.075 g, 43%) as a brownsolid.

Example 122N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(3-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound LXXXI)

A solution of intermediate 43 (0.075 g, 0.14 mmol) in DCM (8 mL) wastreated with TFA (2 mL). After 2 h of stirring, solvents were removedand resulting residue was triturated with diethyl ether resulting inwhite hygroscopic powder (0.05 g, 82%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 2.89 (br s, 4H), 3.2 (br s,4H), 3.68 (s, 4H), 3.82 (br s, 3H), 7.16-7.19 (m, 2H), 7.28 (t, J=7.9Hz, 1H), 7.33 (d, J=2.3 Hz, 1H), 7.39 (s, 1H), 7.43 (d, J=8.5 Hz, 1H),7.49 (d, 8.6 Hz, 1H), 7.98 (s, 1H), 8.8 (br s, 2H), 9.78 (br s, 1H),10.57 (br s, 1H). MS (ES+): m/z 439 (M+H)⁺.

Example 123N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine(Compound LXXXII)

A mixture of intermediate 31 (0.66 g, 2.3 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.88mg, 3.0 mmol) in acetic acid (15 mL) was microwaved at 160° C. for 15min. The mixture was allowed to cool to room temperature and acetic acidremoved under reduced pressure. The residue was taken in water (20 mL)and the mixture was neutralized with 10% NaOH solution until solidprecipitated. Filtration followed by column chromatography yielded thetitle compound as beige solids (0.51 g, 50%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.37-1.44 (m, 2H), 1.86-1.89 (m, 2H), 2.09(s, 3H), 2.50-2.56 (m, 2H), 2.91-2.95 (m, 2H), 3.16 (s, 3H), 3.32 (br s,3H), 3.72 (s, 3H), 4.09 (br s, 1H), 4.21-4.26 (m, 1H), 6.77 (d, J=9 Hz,2H), 7.27 (d, J=8.5 Hz, 1H), 7.40-7.42 (m, 1H), 7.46-7.49 (m, 3H), 7.87(s, 1H), 8.31 (s, 1H), 8.78 (s, 1H). MS (ES+): m/z 440 (M+H)⁺.

Example 1244-{3-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylicacid tert-butyl ester (Intermediate 44)

A mixture of intermediate 31 (0.13 g, 0.46 mmol) and4-(3-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.19mg, 0.68 mmol) in acetic acid (8 mL) was heated at 80° C. for 15 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken up in water (20 mL) andthe mixture was neutralized with 10% NaOH solution. This was thenextracted with ethyl acetate, washed with brine and evaporated to oilyresidue. Column chromatography yielded the title compound as whitesolids (0.12 g, 48%).

Example 125N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(3-piperazin-1-yl-phenyl)-pyrimidine-2,4-diamine(Compound LXXXIII)

A solution of intermediate 44 (0.11 g, 0.21 mmol) in DCM (8 mL) wastreated with TFA (1 mL). After 3 h of stirring, solvents were removedand resulting residue was taken up in ethyl acetate and washed with 10%sodium bicarbonate solution. Organic phase then dried over sodiumsulfate, filtered and evaporated to white powder. This was diluted withDCM (5 mL) and treated with 4M HCl in dioxane (0.5 mL). Solvents wereimmediately removed affording HCL salt of title compound as white solids(0.06 g, 67%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.18 (s, 3H), 3.12 (br s, 4H), 3.22 (br s,4H), 3.65 (s, 3H), 6.80 (d, J=8.1 Hz, 1H), 6.95 (s, 2H), 7.14 (t, J=8.2Hz, 1H), 7.23 (d, J=7.0 Hz, 1H), 7.37-7.40 (m, 2H), 7.95 (s, 1H), 9.33(br s, 2H), 9.88 (s, 1H), 10.62 (s, 1H). MS (ES+): m/z 425 (M+H)⁺.

Example 126 2-[4-(3-Bromo-phenyl)-piperidin-1-yl]-ethanol (Intermediate45)

4-(3-Bromo-phenyl)-piperidine (1.2 g, 4.8 mmol) and 2-bromoethanol (0.72mL, 10 mmol) were diluted with DMF (20 mL) and treated with potassiumcarbonate (2.7 g, 20 mmol). These were stirred at ambient temperaturefor 18 then poured onto water and extracted with ethyl acetate. Organicphase then washed with brine, dried over sodium sulfate, filtered andevaporated to clear oil (0.6 g, 44%).

Example 1272-[4-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-piperidin-1-yl]-ethanol(Compound LXXXIV)

A mixture of intermediate 32 (0.11 g, 0.38 mmol), intermediate 45 (0.21g, 0.75 mmol), Pd₂(dba)₃ (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075mmol) and cesium carbonate (0.37 g, 1.1 mmol) was suspended in dioxane(10 mL) and microwaved at 160° C. for 15 min. The reaction mixture wascooled to room temperature and centrifuged down. The reaction wasdecanted and the organic phase concentrated in vacuo. The residue waspurified by HPLC to afford the title compound (0.075 g, 43%) as a purplesolid (0.02 g, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.60-1.67 (m, 2H), 1.73 (d, J=11.3 Hz, 2H),2.02-2.07 (m, 2H), 2.08 (s, 3H), 2.21 (s, 3H), 2.39-2.45 (m, 7H), 2.95(d, J=11.4 Hz, 2H), 3.00 (t, J=4.66 Hz, 4H), 3.50 (t, J=6.44 Hz, 2H),6.76 (d, J=9 Hz, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.22 (t, J=7.8 Hz, 1H),7.45-7.49 (m, 3H), 7.66 (d, J=7.7 Hz, 1H), 7.82 (s, 1H), 8.09 (s, 1H),8.67 (s, 1H). MS (ES+): m/z 502 (M+H)⁺.

Example 128 4-(3-Bromo-benzenesulfonylamino)-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 46)

3-Bromo-benzenesulfonyl chloride (2.2 g, 8.7 mmol) and4-amino-piperidine-1-carboxylic acid tert-butyl ester (2 g, 10 mmol)were combined and diluted with DCM (50 mL) and TEA (3.6 mL, 26 mmol).After 16 h, reaction was poured into separatory funnel and washed withwater. Organic phase was then washed with brine, dried over sodiumsulfate, filtered and evaporated to clear oil which solidified uponstanding (3.6 g, 98%).

Example 1294-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonylamino)-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 47)

A mixture of intermediate 32 (0.15 g, 0.518 mmol), intermediate 46 (0.28g, 0.67 mmol), Pd₂(dba)₃ (0.024 g, 0.026 mmol), Xantphos (0.03 g, 0.052mmol) and cesium carbonate (0.34 g, 1 mmol) was suspended in dioxane (10mL) and microwaved at 160° C. for 15 min. The reaction mixture wascooled to room temperature and centrifuged down. The reaction wasdecanted onto ice. Resulting precipitate dried and carried on directlyfor deprotection step (0.2 g).

Example 1303-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N-piperidin-4-yl-benzenesulfonamide(Compound LXXXV)

Intermediate 47 (0.2 g, 0.32 mmol) was diluted with DCM (10 mL) andtreated with TFA (0.3 mL). After 3 h, reaction solvents removed andresulting residue was purified by HPLC (0.01 g, 6%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.30-1.35 (m, 2H), 1.56-1.58 (m, 2H), 1.98(s, 2H), 2.11 (s, 3H), 2.21 (s, 3H), 2.43-2.45 (m, 4H), 2.84-2.87 (m,2H), 3.02 (t, J=4.6 Hz, 2H), 6.80 (d, J=9 Hz, 2H), 7.45-7.51 (m, 4H),7.78 (br s, 1H), 7.88 (s, 1H), 8.05 (s, 1H), 8.20 (d, J=7.6 Hz, 1H),8.53 (s, 1H), 8.71 (s, 1H). MS (ES+): m/z 537 (M+H)⁺.

Example 131N⁴-(4-(Trifluoromethyl)-3-methylphenyl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diaminehydrochloride (Compound LXXXVI)

A suspension of intermediate 32 (0.12 g, 0.40 mmol),1-bromo-3-(trifluoromethyl)-2-methylbenzene (0.14 g, 0.59 mmol),Pd₂(dba)₃ (37 mg, 0.04 mmol), Xantphos (47 mg, 0.08 mmol) and cesiumcarbonate (0.39 g, 1.20 mmol) in dioxane (20 mL) was degassed with argonfor 2 min then refluxed in a sealed tube for overnight. After cooling toroom temperature, the solvent was removed by rotovap and the resultingmixture was purified by silica gel with 10% CH₃OH/CHCl₃ as an eluent toafford the title compound as a white solid. The white was dissolved inCHCl₃ (30 mL) and titrated with 2 M HCl in dioxane to pH 1. The solventwas removed by rotovap and the solid was recrystalized from acetone (25mg, 13%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.20 (s, 3H), 2.26 (s, 3H), 2.77 (d, J=4.5Hz, 3H), 3.00-3.20 (m, 4H), 3.45 (d, J=11.6 Hz, 2H), 3.63 (d, J=12.2 Hz,2H), 6.71 (d, J=8.1 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 7.55 (t, J=7.9 Hz,1H), 7.63 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.77 Hz, 1H), 7.94 (s, 1H),10.13 (s, 1H), 10.60 (s, 1H), 11.28 (s, 1H). MS (ES+): m/z 457 (M+H)⁺.

Example 1325-Methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(3-(methylsulfonyl)phenyl)-pyrimidine-2,4-diamine(Compound LXXXVII)

A suspension of intermediate 32 (0.13 g, 0.44 mmol),1-bromo-3-(methylsulfonyl)benzene (0.24 g, 1.0 mmol), Pd₂(dba)₃ (40 mg,0.04 mmol), Xantphos (50 mg, 0.08 mmol) and cesium carbonate (0.43 g,1.32 mmol) in dioxane (50 mL) was degassed with argon for 2 min thenrefluxed for overnight. After cooling to room temperature, the solventwas removed by rotovap and the resulting mixture was purified by silicagel with 30% CH₃OH/CHCl₃ as an eluent to afford the title compound aspale yellow solid (35 mg, 15%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.23 (s, 3H), 2.46 (br s,4H), 3.03 (t, J=4.4 Hz, 4H), 3.19 (s, 3H), 6.81 (d, J=9.0 Hz, 2H), 7.45(d, J=8.9 Hz, 2H), 7.5-7.6 (m, 2H), 7.91 (s, 1H), 8.05 (s, 1H), 8.36 (d,J=6.7 Hz, 1H), 8.60 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z 453 (M+H)⁺.

Example 133 1-Bromo-3-(propylsulfonyl)benzene (Intermediate 48)

To a solution of 3-bromobenzenethiol (0.50 g, 2.6 mmol) in dioxane (50mL) was added 1-iodopropane (1.1 g, 6.5 mmol) and cesium carbonate (2.2g, 6.8 mmol) was stirred at reflux until all 3-bromobenzenethiolreacted. The reaction was quenched with saturated NaHCO₃ solution (25mL) and the mixture extracted with CHCl₃ (60 mL). The product in theCHCl₃ was refluxed with mCPBA (2.9 g, 13 mmol) until all startingreacted. The organic layer was washed with 2M NaOH to remove the excessof mCPBA, dried over Na₂SO₄ and filtered. The filtrate was concentratedand the crude product was purified with silica gel column with 1:1hexanes/CHCl₃ as an eluent to yield colorless oil (0.30 g, 43% in2-steps).

¹H NMR (500 MHz, DMSO-d₆): 0.92 (t, J=7.4 Hz, 3H), 1.52-1.60 (m, 2H),3.35-3.38 (m, 2H), 7.63 (t, J=8.0 Hz, 1H), 7.88-7.91 (m, 1H), 7.95-7.98(m, 1H), 8.04 (t, J=1.8 Hz, 1H).

Example 1345-Methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(3-(propylsulfonyl)phenyl)-pyrimidine-2,4-diaminehydrochloride (Compound LXXXVIII)

A suspension of intermediate 32 (0.25 g, 0.84 mmol), intermediate 48(0.26 g, 1 mmol), Pd₂(dba)₃ (8 mg, 0.01 mmol), Xantphos (16 mg, 0.03mmol) and cesium carbonate (0.82 g, 2.52 mmol) in dioxane (50 mL) wasdegassed with argon for 2 min then refluxed for overnight. After coolingto room temperature, the solvent was removed by rotovap and theresulting mixture was purified by silica gel with 10% CH₃OH/CHCl₃ as aneluent to afford the title compound as a white solid. The white wasdissolved in CHCl₃ (30 mL) and titrated with 2 M HCl in dioxane to pH 1.The solvent was removed by rotovap and the solid was recrystalized frommethanol (65 mg, 15%).

¹H NMR (500 MHz, DMSO-d₆): 0.90 (t, J=7.4 Hz, 3H), 1.50-1.60 (m, 2H),2.18 (s, 3H), 2.81 (s, 3H), 3.00-3.13 (m, 4H), 3.27 (t, J=7.7 Hz, 2H),3.48 (d, J=10.9 Hz, 2H), 3.75 (d, J=11.4 Hz, 2H), 6.95 (d, J=8.8 Hz,2H), 7.27 (d, J=8.9 Hz, 2H), 7.64 (t, J=8.0 Hz, 1H), 7.73 (d, J=7.8 Hz,1H), 7.93 (s, 1H), 8.00 (s, 1H), 8.07 (s, 1H), 9.92 (s, 1H), 10.36 (s,1H), 10.99 (s, 1H). MS (ES+): m/z 481 (M+H)⁺.

Example 135 3-(Morpholinomethyl)benzenamine (Intermediate 49)

Zinc chloride (0.1 g, 0.73 mmol) was added to the solution of3-nitrobenzaldehyde (5.9 g, 39.02 mmol), morpholine (3.4 g, 39.02 mmol),sodium cyanoborohydride (2.7 g, 43 mmol) in methanol (50 mL) at roomtemperature. The solution was heated to reflux for 1 hour. After coolingdown , the reaction was quenched by water (2 mL) and the methanol wasremoved by rotovap. The crude product was dissolved in 2M NaOH (50 mL)and extracted by CHCl₃, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated under vacuum.

The above crude product in methanol (200 mL) was reduced by Raney Ni andhydrazine at room temperature. The reaction was monitored by TLC inethyl acetate. After all starting material reacted, the methanol wasremoved by rotovap. The crude was purified by silica gel with ethylacetate as an eluent to yield a white solid (1.5 g, 50% in 2-steps).

¹H NMR (500 MHz, DMSO-d₆): 2.31 (s, 4H), 3.28 (s, 2H), 3.56 (t, J=4.6Hz, 4H), 4.97 (s, 2H), 6.40-6.45 (m, 2H), 6.53 (t, J=1.8 Hz, 1H), 6.93(t, J=7.7 Hz, 1H).

Example 1365-Methyl-N²-(3-(morpholinomethyl)phenyl)pyrimidine-2,4-diamine(Intermediate 50)

A mixture of 2-chloro-5-methylpyrimidin-4-amine (0.17 g, 1.17 mmol) andintermediate 49 (0.25 g, 1.30 mmol) was suspended in acetic acid (10 mL)and heated at 100° C. for 2 h. The mixture was allowed to cool to roomtemperature and acetic acid removed under reduced pressure. The residuewas taken in water (20 mL) and neutralized to pH˜8. The resultingsolution was extracted with CHCl₃ (100 mL) and the organic layerseparated. The organic layer was washed with brine, dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo and the crudeproduct purified by silica gel column with 10% CH₃OH/EtOAc as an eluentto afford the title compound as oil (0.15 g, 43%).

¹H NMR (500 MHz, DMSO-d₆): 1.91 (s, 3H), 2.35 (s, 4H), 3.17 (s, 2H),3.57(t, J=4.4 Hz, 4H), 6.37 (s, 2H), 6.78 (d, J=7.5 Hz, 1H), 7.13 (t,J=7.8 Hz, 1H), 7.59 (s, 1H), 7.69 (s, 1H), 7.74 (d, J=9.3 Hz, 1H), 8.68(s, 1H).

Example 137N-tert-Butyl-3-[5-methyl-2-(3-morpholin-4-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamidehydrochloride (Compound LXXXIX)

A suspension of intermediate 50 (1.0 g, 3.42 mmol),3-bromo-N-tert-butyl-benzenesulfonamide (1.28 g, 4.28 mmol), Pd₂(dba)₃(30 mg, 0.03 mmol), Xantphos (40 mg, 0.07 mmol) and cesium carbonate(3.34 g, 10.24 mmol) in dioxane (50 mL) was degassed with argon for 2min then refluxed for overnight. After cooling to room temperature, thesolvent was removed by rotovap and the resulting mixture was purified bysilica gel with 10% CH₃OH/CHCl₃ as an eluent to afford the titlecompound as a white solid. The white was dissolved in hot dioxane (150mL) and titrated with 2 M HCl in dioxane to pH 1. The solvent wasremoved by rotovap and the solid was recrystalized from methanol (0.15g, 8%).

¹H NMR (500 MHz, DMSO-d₆): 1.08 (s, 9H), 2.20 (s, 3H), 3.0-3.2 (m, 4H),3.7-4.0 (m, 4H), 4.23 (s, 2H), 7.33 (t, J=7.9 Hz, 1H), 7.38 (d, J=7.7Hz, 1H), 7.48 (s, 1H), 7.55-7.65 (m, 3H), 7.71 (d, J=7.9 Hz, 1H), 7.90(d, J=7.4 Hz, 1H), 8.01 (s, 1H), 9.96 (br s, 1H), 10.61 (br s, 1H),11.31 (br s, 1H). MS (ES+): m/z 511 (M+H)⁺.

Example 138 2-Chloro-5-methyl-N-(3,5-dimethylphenyl)pyrimidin-4-amine(Intermediate 51)

A mixture of 1-bromo-3,5-dimethylbenzene (104 μL, 0.77 mmol),2-chloro-5-methyl-pyrimidin-4-ylamine (104 mg, 0.72 mmol), Pd(OAC)₂ (15mg, 0.07 mmol), Xantphos (83 mg, 0.14 mmol) and potassium tert-butoxide(159 mg, 1.42 mmol) in dioxane (8 mL) was microwaved at 160° C. for 20min. The reaction mixture was cooled to room temperature and filteredrinsing with DCM and methanol. The filtrate was concentrated andpurified using gradient flash chromatography (0-100% ethyl acetate inhexanes) to afford the title compound as a yellow oil (89 mg, 50%). MS(ES+): m/z 248 (M+H)⁺.

Example 1395-Methyl-N⁴-(3,5-dimethylphenyl)-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound XC)

A mixture of intermediate 51 (89 mg, 0.36 mmol), and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (139mg, 0.47 mmol) in acetic acid was stirred at room temperature for 16 h,then heated to 95° C. for 2 h. The reaction mixture was concentrated invacuo, and purified by preparative HPLC. The product was basified withNaHCO₃ (aq)(10 mL) and extracted with ethyl acetate (3×30 mL). Thecombined organic layers were washed with brine (5 mL), dried (Na₂SO₄),and concentrated. The freebase was taken up in MeOH (5 mL) and conc HCl(5 drops) and after 2 min was concentrated in vacuo in the presence ofDCM and hexanes to afford the HCl salt of the title compound as anoff-white solid (63 mg, 40%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.72-1.83 (m, 2H), 2.02-2.08 (m, 2H), 2.14(d, J=0.6 Hz, 3H), 2.24 (s, 6H), 3.04-3.15 (m, 2H), 3.21-3.31 (m, 2H),4.57-4.60 (m, 1H), 6.85 (s, 1H), 6.91 (d, J=8.9 Hz, 2H), 7.20 (s, 2H),7.37 (d, J=8.9 Hz, 2H), 7.85 (s, 1H), 8.50 (br s, 1H), 8.56 (br s, 1H),9.36 (br s, 1H), 10.10 (br s, 1H). MS (ES+): m/z 404 (M+H)⁺.

Example 140 2-Chloro-N-(3,5-dimethoxyphenyl)-5-methylpyrimidin-4-amine(Intermediate 52)

A mixture of 1-bromo-3,5-dimethoxybenzene (436 mg, 2.01 mmol),2-chloro-5-methyl-pyrimidin-4-ylamine (287 mg, 2.00 mmol), Pd(OAc)₂ (44mg, 0.20 mmol), Xantphos (237 mg, 0.41 mmol) and potassium tert-butoxide(448 mg, 3.99 mmol) in dioxane (15 mL) and DMF (5 mL) was microwaved at160° C. for 20 min. The reaction mixture was cooled to room temperatureand filtered rinsing with DCM and methanol. The filtrate wasconcentrated and purified using gradient flash chromatography (0-100%ethyl acetate in hexanes) to afford the title compound as a yellow solid(182 mg, 33%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.17 (s, 3H), 3.74 (s, 6H), 6.27 (t, J=2.2Hz, 1H), 6.99 (d, J=2.2 Hz, 2H), 8.06 (s, 1H), 8.71 (s, 1H). MS (ES+):m/z 280 (M+H)⁺.

Example 141N⁴-(3,5-Dimethoxyphenyl)-5-methyl-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound XCI)

A mixture of intermediate 52 (100 mg, 0.36 mmol), and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (106mg, 0.36 mmol) in acetic acid was heated to 95° C. for 2 h. The reactionmixture was concentrated in vacuo, and purified by preparative HPLC toafford the TFA salt of the title compound as a tan solid (75 mg, 39%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.74-1.83 (m, 2H), 2.03-2.11 (m, 2H), 2.15(s, 3H), 3.06-3.15 (m, 2H), 3.21-3.30 (m, 2H), 3.69 (s, 6H), 4.57-4.60(m, 1H), 6.39 (t, J=2.2 Hz, 1H), 6.80 (d, J=2.2 Hz, 2H), 6.89 (d, J=8.9Hz, 2H), 7.37 (d, J=9.0 Hz, 2H), 7.86 (s, 1H), 8.53 (br s, 1H), 8.58 (brs, 1H), 9.49 (br s, 1H), 10.24 (br s, 1H). MS (ES+): m/z 436 (M+H)⁺.

Example 1425-Methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)-N⁴-(3-(piperidin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound XCII)

A mixture of 1-(3-bromophenyl)piperidine (91 mg, 0.38 mmol),intermediate 32 (99 mg, 0.33 mmol), Pd₂(dba)₃ (15 mg, 0.02 mmol),Xantphos (24 mg, 0.04 mmol) and cesium carbonate (219 mg, 0.67 mmol) indioxane (4 mL) was microwaved at 160° C. for 15 min. The reactionmixture was cooled to room temperature, concentrated in vacuo, taken upin methanol, and filtered rinsing with DCM and methanol. The filtratewas concentrated and purified by preparative HPLC to afford the TFA saltof the title compound as an off-white solid (14 mg, 8%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.47-1.53 (m, 2H), 1.56-1.61 (m, 4H), 2.07(s, 3H), 2.21 (s, 3H), 2.44 (t, J=4.9 Hz, 4H), 3.01 (t, J=4.9 Hz, 4H),3.08 (t, J=5.4 Hz, 4H), 6.63 (dd, J=8.2, 2.3 Hz, 1H), 6.76 (d, J=9.0 Hz,2H), 7.12 (t, J=8.3 Hz, 1H), 7.14 (s, 1H), 7.27 (d, J=7.6 Hz, 1H), 7.50(d, J=9.0 Hz, 2H), 7.81 (s, 1H), 8.00 (s, 1H), 8.67 (s, 1H). MS (ES+):m/z 458 (M+H)⁺.

Example 143N⁴-(3-(1H-Pyrrol-1-yl)phenyl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound XCIII)

A mixture of 1-(3-bromophenyl)-1H-pyrrole (86 mg, 0.39 mmol),intermediate 32 (99 mg, 0.33 mmol), Pd₂(dba)₃ (16 mg, 0.02 mmol),Xantphos (26 mg, 0.05 mmol) and cesium carbonate (215 mg, 0.66 mmol) indioxane (4 mL) was microwaved at 160° C. for 15 min. The reactionmixture was cooled to room temperature, concentrated in vacuo, taken upin methanol, and filtered rinsing with DCM and methanol. The filtratewas concentrated and purified by preparative HPLC to afford the TFA saltof the title compound as an off-white solid (32 mg, 18%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.21 (s, 3H), 2.42 (t, J=4.9Hz, 4H), 2.95 (t, J=4.9 Hz, 4H), 6.24 (t, J=2.2 Hz, 2H), 6.58 (d, J=8.9Hz, 2H), 7.23 (dd, J=7.8, 1.8 Hz, 1H), 7.31 (t, J=2.2 Hz, 2H), 7.37 (t,J=8.1 Hz, 1H), 7.43 (d, J=9.0 Hz, 2H), 7.60 (d, J=8.8 Hz, 1H), 7.86 (t,J=2.2 Hz, 1H), 7.87 (s, 1H), 8.30 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z440 (M+H)⁺.

Example 1445-{2-[4-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-indole-1-carboxylicacid tert-butyl ester (Intermediate 53)

A mixture of tert-butyl 5-bromo-1H-indole-1-carboxylate (161 mg, 0.54mmol), intermediate 42 (202 mg, 0.50 mmol), Pd₂(dba)₃ (29 mg, 0.03mmol), Xantphos (36 mg, 0.07 mmol) and cesium carbonate (321 mg, 0.98mmol) in dioxane (5 mL) was microwaved at 160° C. for 20 min. Thereaction mixture was cooled to room temperature and filtered rinsingwith DCM. The filtrate was concentrated and purified by gradient flashchromatography (0-20% MeOH in DCM) to afford the title compound as alight-brown solid (290 mg, 94%). MS (ES+): m/z 615 (M+H)⁺.

Example 145N⁴-(1H-Indol-5-yl)-5-methyl-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound XCIV)

To a solution of acetyl chloride (670 μL, 9.42 mmol) in methanol (22 mL)was added intermediate 53 (290 mg, 0.47 mmol), and the reaction mixturewas heated to 60° C. for 4 h. The mixture was concentrated in vacuo andpurified by preparative HPLC to afford the TFA salt of the titlecompound as a brown solid (6 mg, 2%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.70-1.78 (m, 2H), 1.98-2.07 (m, 2H), 2.16(s, 3H), 3.02-3.11 (m, 2H), 3.21-3.30 (m, 2H), 4.44-4.53 (m, 1H), 6.43(s, 1H), 6.75 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.4 Hz, 1H), 7.31 (d, J=8.7Hz, 2H), 7.40-7.42 (m, 2H), 7.71 (s, 1H), 7.78 (s, 1H), 8.48 (br s, 1H),8.54 (br s, 1H), 9.65 (br s, 1H), 9.99 (br s, 1H), 11.18 (s, 1H). MS(ES+): m/z 415 (M+H)⁺.

Example 146N4-(4-Chloro-3-methoxy-phenyl)-5-methyl-N2-(6-piperazin-1-yl-pyridin-3-yl)-pyrimidine-2,4-diamine(Compound XCV)

A mixture of intermediate 31 (0.10 g, 0.35 mmol),4-(5-amino-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester(0.10 g, 0.36 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), Xantphos (35 mg,0.06 mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1,4 mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 170° C. for 30 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM and the filtrate concentrated. The residue waspurified by flash chromatography on silica gel (hexanes to EtOAc) toafford the Boc-protected precursor. To a solution of the precursor inDCM (5 mL) was added TFA (3 mL). The mixture was stirred at roomtemperature for 30 min, concentrated and the residue purified by HPLC.The corrected fractions were combined and poured into saturated NaHCO₃solution (30 mL). The combined aqueous layers were extracted with EtOAc(2×30 mL) and the combined organic layers washed with brine, dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated and theresulting solid triturated in a mixture of hexanes/EtOAc (10/1, 55 mL).After filtration, the title compound was obtained as a white solid (20mg, 13%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.09 (s, 3H), 2.81 (t, J=5.0 Hz, 4H),3.29-3.31 (m, 4H), 3.73 (s, 3H), 6.70 (d, J=9.1 Hz, 1H), 7.26 (d, J=8.6Hz, 1H), 7.42 (d, J=9.1 Hz, 1H), 7.49 (d, J=2.2 Hz, 1H), 7.76 (dd,J=9.1, 2.6 Hz, 1H), 7.86 (s, 1H), 8.29 (s, 1H), 8.31 (d, J=2.6 Hz, 1H),8.71 (s, 1H). MS (ES+): m/z 426 (M+H)⁺.

Example 147 4-(4-Amino-2-methoxycarbonyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (Intermediate 54)

To a solution of4-(2-methoxycarbonyl-4-nitro-phenyl)-piperazine-1-carboxylic acidtert-butyl ester (1.0 g, 2.7 mmol) in MeOH (30 mL) was added 10 wt %Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuatedand then refilled with hydrogen (3 cycles) and stirred at roomtemperature for 2 h. The heterogeneous reaction mixture was filteredthrough a pad of Celite, washed with MeOH and concentrated in vacuo. Thecrude amino-compound was used in the next step without purification. MS(ES+): m/z 336 (M+H)⁺.

Example 1485-[4-(4-Chloro-3-methoxy-phenylamino)-5-methyl-pyrimidin-2-ylamino]-2-piperazin-1-yl-benzoicacid methyl ester (Compound XCVI)

A mixture of intermediate 31 (0.10 g, 0.35 mmol), intermediate 54 (0.14g, 0.42 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06mmol) and cesium carbonate (0.23 g, 0.71 mmol) was suspended in dioxane(15 mL) and heated at reflux under the argon atmosphere for 2.5 h. Thereaction mixture was cooled to room temperature and diluted with DCM (30mL). The mixture was filtered and the filtrate concentrated. The residuewas purified by flash chromatography on silica gel (hexanes to 60%EtOAc/hexanes) to afford the Boc-protected precursor. To a solution ofthe precursor in DCM (5 mL) was added TFA (2 mL). The mixture wasstirred at room temperature for 1 h, concentrated and the residuepurified by HPLC. The corrected fractions were combined and poured intosaturated NaHCO₃ solution (30 mL). The combined aqueous layers wereextracted with EtOAc (2×30 mL) and the combined organic layers washedwith brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated and then taken up in minimum amount of EtOAc. Hexanes wereadded until solid precipitated. After filtration, the title compound wasobtained as a white solid (40 mg, 24%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.80-2.90 (m, 8H), 3.73 (s,3H), 3.74 (s, 3H), 6.98 (d, J=8.9 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H),7.40-7.48 (m, 2H), 7.69 (dd, J=8.9, 2.6 Hz, 1H), 7.90 (d, J=2.6 Hz, 1H),7.91 (s, 1H), 8.36 (s, 1H), 9.04 (s, 1H). MS (ES+): m/z 483 (M+H)⁺.

Example 149 5-Amino-2-(2-pyrrolidin-1-yl-ethoxy)-benzoic acid methylester (Intermediate 55)

A suspension of 5-amino-2-hydroxy-benzoic acid methyl ester (1.0 g, 6.0mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (1.2 g, 7.1 mmol)and cesium carbonate (5.0 g, 15 mmol) in DMF (40 mL) was heated at 60°C. for 17 h. The mixture was allowed to cool to room temperature, pouredinto water (60 mL) and extracted with EtOAc (2×50 mL). The combinedextracts were washed with brine, dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated and the residue purified byflash chromatography on silica gel (DCM to 30% MeOH/DCM) to afford thetitle compound (0.2 g, 13%) as a light brown solid. MS (ES+): m/z 265(M+H)⁺.

Example 1505-[4-(Benzo[1,3]dioxol-4-ylamino)-5-methyl-pyrimidin-2-ylamino]-2-(2-pyrrolidin-1-yl-ethoxy)-benzoicacid methyl ester (Compound XCVII)

A mixture of intermediate 30 (0.15 g, 0.57 mmol), intermediate 55 (0.20g, 0.75 mmol), Pd₂(dba)₃ (50 mg, 0.055 mmol), Xantphos (60 mg, 0.10mmol) and cesium carbonate (0.30 g, 0.92 mmol) in dioxane/DMF (3/1, 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM, the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthen taken up in minimum amount of EtOAc. Hexanes were added until solidprecipitated. After filtration, the title compound was obtained as anoff white solid (30 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.72 (m, 4H), 2.07 (s, 3H), 2.50-2.62(m, 4H), 2.75-2.85 (m, 2H), 3.73 (s, 3H), 4.02 (t, J=5.8 Hz, 2H), 5.88(s, 2H), 6.78-6.88 (m, 3H), 6.92 (dd, J=8.0, 2.1 Hz, 1H), 7.75-7.80 (m,2H), 7.83 (s, 1H), 8.22 (s, 1H), 8.89 (s, 1H). MS (ES+): m/z 492 (M+H)⁺.

Example 151N-tert-Butyl-3-{5-methyl-2-[4-(piperidin-4-yloxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound XCVIII)

A mixture of intermediate 33 (0.15 g, 0.42 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.15g, 0.51 mmol) in acetic acid (3 mL) was sealed in a microwave reactiontube and irradiated with microwave at 150° C. for 20 min. After coolingto room temperature, the cap was removed and the mixture concentrated.The residue was taken in water (20 mL) and the pH adjusted with 10% NaOHsolution until solid precipitated. The solid was filtered and thenpurified by HPLC. The corrected fractions were combined, poured intosaturated NaHCO₃ solution (30 mL) and extracted with EtOAc (2×30 mL).The combined extracts were washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and then taken up inminimum amount of EtOAc. Hexanes were added until solid precipitated.After filtration, the title compound was obtained as a white solid (20mg, 9%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 1.65-1.73 (m, 2H), 1.95-2.05(m, 2H), 2.12 (s, 3H), 2.89-2.95 (m, 2H), 3.10-3.20 (m, 2H), 4.40-4.45(m, 1H), 6.84 (d, J=9.1 Hz, 2H), 7.45-7.60 (m, 6H), 7.90 (s, 1H),8.10-8.15 (m, 2H), 8.55 (s, 1H), 8.81 (s, 1H). MS (ES+): m/z 511 (M+H)⁺.

Example 152 2-(5-Amino-pyridin-2-yloxy)-ethanol (Intermediate 56)

To a solution of 2-(5-nitro-pyridin-2-yloxy)-ethanol (1.0 g, 5.4 mmol)in MeOH (30 mL) was added 10 wt % Pd/C (0.1 equiv by wt) under argonatmosphere. The mixture was evacuated and then refilled with hydrogen (3cycles) and stirred at room temperature for 1 h. The heterogeneousreaction mixture was filtered through a pad of Celite, washed with MeOHand concentrated in vacuo. The crude amino-compound was used in the nextstep without purification. MS (ES+): m/z 155 (M+H)⁺.

Example 1532-{5-[4-(Benzo[1,3]dioxol-4-ylamino)-5-methyl-pyrimidin-2-ylamino]-pyridin-2-yloxy}-ethanol(Compound XCIX)

A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 56 (0.10g, 0.65 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06mmol) and cesium carbonate (0.26 g, 0.80 mmol) in dioxane/DMF (3/1, 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM, the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthen taken up in minimum amount of EtOAc. Hexanes were added until solidprecipitated. After filtration, the title compound was obtained as anoff white solid (50 mg, 35%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.06 (s, 3H), 3.66 (q, J=5.4 Hz, 2H), 4.15(t, J=5.2 Hz, 2H), 4.77 (t, J=5.5 Hz, 2H), 5.91 (s, 2H), 6.52 (d, J=9.0Hz, 1H), 6.78-6.90 (m, 3H), 7.82 (s, 1H), 7.96 (dd, J=8.9, 2.7 Hz, 1H),8.22 (d, J=2.6 Hz, 1H), 8.27 (s, 1H), 8.84 (s, 1H). MS (ES+): m/z 382(M+H)⁺.

Example 154 1-[2-(2-Methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine(Intermediate 57)

A suspension of potassium 2-methoxy-4-nitro-phenolate (2.0 g, 9.7 mmol),1-(2-chloro-ethyl)-pyrrolidine hydrochloride (2.0 g, 12 mmol) and cesiumcarbonate (7.0, 22 mmol) in DMF (35 mL) was heated at 80° C. for 16 h.The mixture was allowed to cool to room temperature, poured into water(60 mL) and extracted with EtOAc (2×50 mL). The combined extracts werewashed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and used in the next step withoutpurification.

MS (ES+): m/z 267 (M+H)⁺.

Example 155 3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(Intermediate 58)

To a solution of intermediate 57 (1.7 g, 6.4 mmol) in MeOH (30 mL) wasadded 10 wt % Pd/C (0.1 equiv by wt) under argon atmosphere. The mixturewas evacuated and then refilled with hydrogen (3 cycles) and stirred atroom temperature for 1 h. The heterogeneous reaction mixture wasfiltered through a pad of Celite, washed with MeOH and concentrated invacuo. The crude amino-compound was used in the next step withoutpurification. MS (ES+): m/z 237 (M+H)⁺.

Example 156N⁴-Benzo[1,3]dioxol-4-yl-N²-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-methyl-pyrimidine-2,4-diamine(Compound C)

A mixture of intermediate 30 (0.10 g, 0.38 mmol), intermediate 58 (0.11g, 0.46 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06mmol) and cesium carbonate (0.25 g, 0.77 mmol) in dioxane/DMF (3/1, 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM, the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthen taken up in minimum amount of EtOAc. Hexanes were added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (50 mg, 28%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.72 (m, 4H), 2.06 (s, 3H), 2.50-2.62(m, 4H), 2.75-2.85 (m, 2H), 3.50 (s, 3H), 3.94 (t, J=6.1 Hz, 2H), 5.84(s, 2H), 6.67 (d, J=8.8 Hz, 1H), 6.78 (dd, J=7.8, 1.1 Hz, 1H), 6.83 (t,J=7.9 Hz, 1H), 6.92 (dd, J=8.1, 1.1 Hz, 1H), 7.14 (dd, J=8.7, 2.4 Hz,1H), 7.23(d, J=2.4 Hz, 1H), 7.83 (s, 1H), 8.21 (s, 1H), 8.69 (s, 1H). MS(ES+): m/z 464 (M+H)⁺.

Example 157N-tert-Butyl-3-[2-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CI)

A mixture of intermediate 33 (0.40 g, 1.1 mmol),4-imidazol-1-yl-phenylamine (0.20 g, 1.3 mmol), Pd₂(dba)₃ (0.10 g, 0.11mmol), Xantphos (0.12 g, 0.21 mmol) and cesium carbonate (0.80 g, 2.5mmol) in dioxane/DMF (3/1, 8 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 160° C. for 30 min. After cooling toroom temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (40 mL). Thecombined aqueous layers were extracted with EtOAc (2×40 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as an off white solid (0.15g, 28%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.15 (s, 3H), 7.07 (s, 1H),7.43 (d, J=9.0 Hz, 2H), 7.50-7.60 (m, 3H), 7.61 (s, 1H), 7.79 (d, J=9.0Hz, 2H), 7.98 (s, 1H), 8.08-8.13 (m, 3H), 8.64 (s, 1H), 9.19 (s, 1H). MS(ES+): m/z 478 (M+H)⁺.

Example 158N-tert-Butyl-3-[2-(4-imidazol-1-ylmethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-imidazol-1-ylmethyl-phenylamine (60 mg, 0.35 mmol), Pd₂(dba)₃ (25 mg,0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g,0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reactiontube and irradiated with microwave at 160° C. for 20 min. After coolingto room temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (40 mg,29%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 5.07 (s, 2H),6.89 (s, 1H), 7.12 (d, J=8.6 Hz, 2H), 7.15 (s, 1H), 7.46 (t, J=7.9 Hz,1H), 7.49-7.52 (m, 1H), 7.56 (s, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.72 (s,1H), 7.94 (s, 1H), 8.09 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.60 (s, 1H),9.02 (s, 1H). MS (ES+): m/z 492 (M+H)⁺.

Example 159 2-(4-Amino-phenoxy)-ethanol (Intermediate 59)

A solution of 2-(4-nitro-phenoxy)-ethanol (2.1 g, 12 mmol) in MeOH (30mL) was flushed with argon and then charged with 10 wt % Pd/C (0.1 equivby wt). The mixture was evacuated under house vacuum and then refilledwith hydrogen from hydrogen balloon. The cycle was repeated again andthe mixture stirred at room temperature for 2 h. The heterogeneousreaction mixture was filtered through a pad of Celite, washed with MeOHand concentrated in vacuo to furnish the title compound (1.8 g, 99%) asa brown solid. MS (ES+): m/z 154 (M+H)⁺.

Example 160N-tert-Butyl-3-{2-[4-(2-hydroxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CIII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 59 (55mg, 0.36 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM, the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthen taken up in minimum amount of EtOAc. Hexanes were added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (15 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.12 (s, 3H), 3.69 (q, J=5.2Hz, 2H), 3.91 (t, J=5.1 Hz, 2H), 4.82 (t, J=5.5 Hz, 2H), 6.80 (d, J=9.1Hz, 2H), 7.45-7.50 (m, 2H), 7.52 (d, J=9.0 Hz, 2H), 7.55 (s, 1H), 7.90(s, 1H), 8.08-8.15 (m, 2H), 8.53 (s, 1H), 8.77 (s, 1H). MS (ES+): m/z472 (M+H)⁺.

Example 161N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-(4-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine(Compound CIV)

A mixture of intermediate 31 (0.10 g, 0.35 mmol),4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.12g, 0.41 mmol), Pd₂(dba)₃ (30 mg, 0.033 mmol), Xantphos (35 mg, 0.06mmol) and cesium carbonate (0.23 g, 0.71 mmol) in dioxane/DMF (3/1, 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM and the filtrate concentrated. The residue waspurified by flash chromatography on silica gel (hexanes to 60%EtOAc/hexanes) to afford the Boc-protected precursor. To a solution ofthe precursor in DCM (5 mL) was added TFA (3 mL). The mixture wasstirred at room temperature for 1 h, concentrated and the residuepurified by HPLC. The corrected fractions were combined and poured intosaturated NaHCO₃ solution (30 mL). The combined aqueous layers wereextracted with EtOAc (2×30 mL) and the combined organic layers washedwith brine, dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated and then taken up in minimum amount of EtOAc. Hexanes wereadded until solid precipitated. After filtration, the title compound wasobtained as a white solid (13 mg, 9%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.11 (s, 3H), 2.30-2.40 (m, 4H), 2.83 (t,J=4.8 Hz, 4H), 3.37 (s, 2H), 3.75 (s, 3H), 7.08 (d, J=8.6 Hz, 2H), 7.29(d, J=8.6 Hz, 1H), 7.43 (dd, J=8.6, 2.2 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H),7.59 (d, J=8.6 Hz, 2H), 7.91 (s, 1H), 8.37 (s, 1H), 8.99 (s, 1H). MS(ES+): m/z 439 (M+H)⁺.

Example 162N-tert-Butyl-3-{5-methyl-2-[4-(2-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CV)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(2-methyl-imidazol-1-yl)-phenylamine (60 mg, 0.35 mmol), Pd₂(dba)₃ (25mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwavereaction tube and irradiated with microwave at 160° C. for 20 min. Aftercooling to room temperature, the cap was removed and the resultingmixture filtered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (30 mg,22%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 2.15 (s, 3H), 2.24 (s, 3H),6.87 (d, J=1.2 Hz, 1H), 7.18 (d, J=1.3 Hz, 1H), 7.22 (d, J=8.9 Hz, 2H),7.50-7.55 (m, 2H), 7.56 (s, 1H), 7.79 (d, J=8.9 Hz, 2H), 7.98 (s, 1H),8.07-8.10 (m, 2H), 8.65 (s, 1H), 9.26 (s, 1H). MS (ES+): m/z 492 (M+H)⁺.

Example 163N-tert-Butyl-3-{5-methyl-2-[4-(2-methyl-imidazol-1-ylmethyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CVI)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(2-methyl-imidazol-1-ylmethyl)-phenylamine (65 mg, 0.35 mmol),Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesiumcarbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 20min. After cooling to room temperature, the cap was removed and theresulting mixture filtered. The filtered solid was washed with DCM, thefiltrate concentrated and the residue purified by HPLC. The correctedfractions were combined and poured into saturated NaHCO₃ solution (30mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) andthe combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and then taken up inminimum amount of EtOAc. Hexanes were added until solid precipitated.After filtration, the title compound was obtained as a white solid (30mg, 21%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.13 (s, 3H), 2.24 (s, 3H),5.01 (s, 2H), 6.73 (d, J=1.2 Hz, 1H), 7.01 (d, J=8.6 Hz, 2H), 7.07 (d,J=1.1 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.48-7.51 (m, 1H), 7.56 (s, 1H),7.62 (d, J=8.6 Hz, 2H), 7.94 (s, 1H), 8.08 (s, 1H), 8.12 (d, J=8.1 Hz,1H), 8.60 (s, 1H), 9.02 (s, 1H). MS (ES+): m/z 506 (M+H)⁺.

Example 164N-tert-Butyl-3-[5-methyl-2-(4-pyridin-4-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CVII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-Pyridin-4-ylmethyl-phenylamine (65 mg, 0.35 mmol), Pd₂(dba)₃ (25 mg,0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g,0.61 mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reactiontube and irradiated with microwave at 160° C. for 20 min. After coolingto room temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (45 mg,32%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 2.13 (s, 3H), 3.87 (s, 2H),7.07 (d, J=8.6 Hz, 2H), 7.22 (d, J=6.0 Hz, 2H), 7.43 (t, J=7.9 Hz, 1H),7.47-7.50 (m, 1H), 7.56 (d, J=6.3 Hz, 2H), 7.58 (s, 1H), 7.93 (s, 1H),8.09 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 8.44 (d, J=5.8 Hz, 2H), 8.58 (s,1H), 8.94 (s, 1H). MS (ES+): m/z 503 (M+H)⁺.

Example 165N-tert-Butyl-3-[5-methyl-2-(4-morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CVIII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-morpholin-4-yl-phenylamine (60 mg, 0.34 mmol), Pd₂(dba)₃ (25 mg, 0.027mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g, 0.61mmol) in dioxane/DMF (3/1, 4 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 160° C. for 20 min. After cooling toroom temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a grey solid (45 mg,32%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.12 (s, 3H), 3.00 (t, J=4.8Hz, 4H), 3.73 (t, J=4.8 Hz, 4H), 6.82 (d, J=9.1 Hz, 2H), 7.45-7.52 (m,4H), 7.56 (s, 1H), 7.89 (s, 1H), 8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.73(s, 1H). MS (ES+): m/z 497 (M+H)⁺.

Example 166N-tert-Butyl-3-[5-methyl-2-(4-[1,2,4]triazol-1-ylmethyl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CIX)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-[1,2,4]triazol-1-ylmethyl-phenylamine (60 mg, 0.34 mmol), Pd₂(dba)₃(25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate(0.20 g, 0.61 mmol) in dioxane (4 mL) was sealed in a microwave reactiontube and irradiated with microwave at 160° C. for 20 min. After coolingto room temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (37 mg,27%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.17 (s, 9H), 2.13 (s, 3H), 5.29 (s, 2H),7.14 (d, J=8.6 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.48-7.51 (m, 1H), 7.56(s, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.94 (s, 1H), 7.95 (s, 1H), 8.08 (s,1H), 8.13 (d, J=8.0 Hz, 1H), 8.59 (s, 1H), 8.60 (s, 1H), 9.04 (s, 1H).MS (ES+): m/z 493 (M+H)⁺.

Example 167N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CX)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(4-methyl-imidazol-1-yl)-phenylamine (60 mg, 0.35 mmol), Pd₂(dba)₃ (25mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20g, 0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 160° C. for 20 min. After cooling toroom temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as an off white solid (20mg, 15%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.15 (s, 3H), 2.16 (s, 3H),7.30 (s, 1H), 7.38 (d, J=9.0 Hz, 2H), 7.50-7.56 (m, 2H), 7.57 (s, 1H),7.76 (d, J=9.0 Hz, 2H), 7.96 (s, 1H), 7.97 (s, 1H), 8.09-8.13 (m, 2H),8.63 (s, 1H), 9.16 (s, 1H). MS (ES+): m/z 492 (M+H)⁺.

Example 168N-tert-Butyl-3-[5-methyl-2-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CXI)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-[1,2,4]triazol-1-yl-phenylamine (55 mg, 0.34 mmol), Pd₂(dba)₃ (25 mg,0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g,0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube andirradiated with microwave at 160° C. for 20 min. After cooling to roomtemperature, the cap was removed and the resulting mixture filtered. Thefiltered solid was washed with DCM, the filtrate concentrated and theresidue purified by HPLC. The corrected fractions were combined andpoured into saturated NaHCO₃ solution (30 mL). The combined aqueouslayers were extracted with EtOAc (2×30 mL) and the combined organiclayers washed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and then taken up in minimum amount of EtOAc.Hexanes were added until solid precipitated. After filtration, the titlecompound was obtained as a white solid (40 mg, 29%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.15 (s, 3H), 7.50-7.58 (m,3H), 7.63 (d, J=9.1 Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 7.99 (s, 1H), 8.09(s, 1H), 8.10-8.15 (m, 1H), 8.17 (s, 1H), 8.66 (s, 1H), 9.12 (s, 1H),9.27 (s, 1H). MS (ES+): m/z 479 (M+H)⁺.

Example 169N-tert-Butyl-3-{5-methyl-2-[3-(1H-tetrazol-5-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),3-(1H-tetrazol-5-yl)-phenylamine (55 mg, 0.34 mmol), Pd₂(dba)₃ (25 mg,0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesium carbonate (0.20 g,0.61 mmol) in dioxane (3 mL) was sealed in a microwave reaction tube andirradiated with microwave at 160° C. for 20 min. After cooling to roomtemperature, the cap was removed and the resulting mixture filtered. Thefiltered solid was washed with DCM, the filtrate concentrated and theresidue purified by HPLC. The corrected fractions were combined andpoured into saturated NaHCO₃ solution (30 mL). The combined aqueouslayers were extracted with EtOAc (2×30 mL) and the combined organiclayers washed with brine, dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated and then taken up in minimum amount of EtOAc.Hexanes were added until solid precipitated. After filtration, the titlecompound was obtained as a white solid (15 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.13 (s, 9H), 2.15 (s, 3H), 7.26 (t, J=7.9Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.44 (dd, J=7.9, 1.1 Hz, 1H), 7.50 (d,J=7.6 Hz, 1H), 7.58 (s, 1H), 7.79 (dd, J=8.1, 1.4 Hz, 1H), 7.98 (s, 1H),8.16 (s, 1H), 8.22 (s, 1H), 8.27 (d, J=7.8 Hz, 1H), 8.57 (s, 1H), 9.08(s, 1H). MS (ES+): m/z 480 (M+H)⁺.

Example 170 4-(1H-Tetrazol-5-yl)-phenylamine (Intermediate 60)

To a solution of 5-(4-nitro-phenyl)-1H-tetrazole (1.0 g, 5.2 mmol) inMeOH (30 mL) was added 10 wt % Pd/C (0.1 equiv by wt) under argonatmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles)and stirred at room temperature for 1.5 h. The heterogeneous reactionmixture was filtered through a pad of Celite, washed with MeOH andconcentrated in vacuo. The crude amino-compound was used in the nextstep without purification. MS (ES+): m/z 162 (M+H)⁺.

Example 171N-tert-Butyl-3-{5-methyl-2-[4-(1H-tetrazol-5-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXIII)

A mixture of intermediate 33 (0.10 g, 0.28 mmol), intermediate 60 (60mg, 0.37 mmol), Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052mmol) and cesium carbonate (0.20 g, 0.61 mmol) in dioxane/DMF (3/1; 4mL) was sealed in a microwave reaction tube and irradiated withmicrowave at 160° C. for 20 min. After cooling to room temperature, thecap was removed and the resulting mixture filtered. The filtered solidwas washed with DCM, the filtrate concentrated and the residue purifiedby HPLC. The corrected fractions were combined and poured into saturatedNaHCO₃ solution (30 mL). The combined aqueous layers were extracted withEtOAc (2×30 mL) and the combined organic layers washed with brine, driedover anhydrous Na₂SO₄ and filtered. The filtrate was concentrated andthen taken up in minimum amount of EtOAc. Hexanes were added until solidprecipitated. After filtration, the title compound was obtained as awhite solid (15 mg, 11%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.13 (s, 9H), 2.16 (s, 3H), 7.52-7.56 (m,2H), 7.57 (s, 1H), 7.83 (s, 4H), 8.01 (s, 1H), 8.08 (s, 1H), 8.13-8.19(m, 1H), 8.69 (s, 1H), 9.34 (s, 1H). MS (ES+): m/z 480 (M+H)⁺.

Example 1723-{2-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-N-tert-butyl-benzenesulfonamide(Compound CXIV)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),1-[4-(4-amino-phenyl)-piperazin-1-yl]-ethanone (80 mg, 0.36 mmol),Pd₂(dba)₃ (25 mg, 0.027 mmol), Xantphos (30 mg, 0.052 mmol) and cesiumcarbonate (0.20 g, 0.61 mmol) in dioxane (3 mL) was sealed in amicrowave reaction tube and irradiated with microwave at 160° C. for 20min. After cooling to room temperature, the cap was removed and theresulting mixture filtered. The filtered solid was washed with DCM, thefiltrate concentrated and the residue purified by HPLC. The correctedfractions were combined and poured into saturated NaHCO₃ solution (30mL). The combined aqueous layers were extracted with EtOAc (2×30 mL) andthe combined organic layers washed with brine, dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated and then taken up inminimum amount of EtOAc. Hexanes were added until solid precipitated.After filtration, the title compound was obtained as an off white solid(55 mg, 37%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 2.04 (s, 3H), 2.12 (s, 3H),2.97 (t, J=5.2 Hz, 2H), 3.03 (t, J=5.1 Hz, 2H), 3.57 (q, J=5.4 Hz, 4H),6.85 (d, J=9.0 Hz, 2H), 7.46-7.52 (m, 4H), 7.56 (s, 1H), 7.90 (s, 1H),8.10-8.17 (m, 2H), 8.52 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 538 (M+H)⁺.

Example 173N-tert-Butyl-3-{5-methyl-2-[4-(1-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXV)

A mixture of intermediate 33 (0.10 g, 0.28 mmol),4-(1-morpholin-4-yl-ethyl)-phenylamine (80 mg, 0.39 mmol), Pd₂(dba)₃ (30mg, 0.033 mmol), Xantphos (35 mg, 0.061 mmol) and cesium carbonate (0.26g, 0.80 mmol) in dioxane (4 mL) was sealed in a microwave reaction tubeand irradiated with microwave at 160° C. for 20 min. After cooling toroom temperature, the cap was removed and the resulting mixturefiltered. The filtered solid was washed with DCM, the filtrateconcentrated and the residue purified by HPLC. The corrected fractionswere combined and poured into saturated NaHCO₃ solution (30 mL). Thecombined aqueous layers were extracted with EtOAc (2×30 mL) and thecombined organic layers washed with brine, dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated and then taken up in minimumamount of EtOAc. Hexanes were added until solid precipitated. Afterfiltration, the title compound was obtained as a white solid (40 mg,27%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (s, 9H), 1.25 (d, J=6.6 Hz, 3H), 2.13(s, 3H), 2.20-2.30 (m, 2H), 2.30-2.40 (m, 2H), 3.24 (q, J=6.6 Hz, 1H),3.54 (t, J=4.4 Hz, 4H), 7.10 (d, J=8.5 Hz, 2H), 7.45-7.52 (m, 2H), 7.55(s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 8.15 (d,J=7.7 Hz, 1H), 8.57 (s, 1H), 8.92 (s, 1H). MS (ES+): m/z 525 (M+H)⁺.

Example 174N⁴-(1H-Indol-4-yl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound CXVI)

A mixture of intermediate 32 (270 mg, 0.9 mmol), 4-bromo-1H-indole (196mg, 0.9 mmol), Pd₂(dba)₃ (91 mg, 0.09 mmol), Xantphos (157 mg, 0.27mmol) and cesium carbonate (1.2 g, 3.6 mmol) were suspended in dioxane(100 mL) and heated at reflux under the argon atmosphere for 20 h. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by HPLC to afford the title compound (55 mg of HCl salt,14%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.22 (s, 3H), 2.79 (d, J=4.3 Hz, 3H),2.98-3.03 (m, 2H), 3.08-3.14 (m, 2H), 3.46-3.48 (m, 2H), 3.64-3.66 (m,2H), 6.35-6.36 (m, 1H), 6.63 (br d, J=8.0 Hz, 1H), 6.98 (d, J=9.1 Hz,2H), 7.05 (d, J=7.4 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.36 (t, J=2.8 Hz,2H), 7.43 (d, J=8.0 Hz, 1H), 7.86 (s, 1H), 10.07 (s, 1H), 10.27 (s, 1H),11.00 (br s, 1H), 11.38 (s, 1H), 12.16 (br s, H). MS (ES+): m/z 414(M+H)⁺.

Example 175 2-Chloro-5-methyl-N-(2,3-dimethylphenyl)pyrimidin-4-amine(Intermediate 61)

A mixture of 2-chloro-5-methylpyrimidin-4-amine (143.6 mg, 1 mmol),1-bromo-2,3-dimethylbenzene (222 mg, 1.2 mmol), Pd₂(dba)₃ (92 mg, 0.1mmol), Xantphos (174 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4 mmol)were suspended in dioxane (150 mL) and heated at reflux under the argonatmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in EtOAc (10 mL) andadded hexanes (100 mL). The solid was collected by filtration and washedwith hexanes to afford the crude title compound as a yellow solid.

Example 1765-Methyl-N⁴-(2,3-dimethylphenyl)-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound CXVII)

A mixture of intermediate 61 (1.0 mmol) and tert-butyl4-(4-aminophenoxy)piperidine-1-carboxylate (292.4 mg, 1.0 mmol) weresuspended in acetic acid (10 mL) and heated at 100° C. for 4 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken in water (20 mL) andneutralized to pH˜7. The resulting solution was extracted with EtOAc (30mL) and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and the crude product purified by HPLC to afford the titlecompound (105 mg of HCl salt, 24%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.76-1.83 (m, 2H), 2.03 (s, 3H), 2.05-2.09(m, 2H), 2.17 (s, 3H), 2.30 (s, 3H), 3.02-3.05 (m, 2H), 3.18 (br s, 2H),4.53-4.56 (m, 1H), 6.72 (d, J=8.5 Hz, 2H), 7.11-7.14 (m, 3H), 7.19-7.24(m, 2H), 7.87 (s, 1H), 9.06 (br s, 1H), 9.13 (br s, 1H), 9.92 (s, 1H),10.43 (s, 1H). MS (ES+): m/z 404 (M+H)⁺.

Example 177N⁴-(4-Chloro-3,5-dimethylphenyl)-5-methyl-N²-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4-diamine(Compound CXVIII)

A mixture of intermediate 32 (240 mg, 0.8 mmol),5-bromo-2-chloro-1,3-dimethylbenzene (212 mg, 0.96 mmol), Pd₂(dba)₃ (92mg, 0.1 mmol), Xantphos (170 mg, 0.3 mmol) and cesium carbonate (1.3 g,4 mmol) were suspended in dioxane (100 mL) and heated at reflux underthe argon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (63 mg of HCl salt, 17%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.15 (s, 3H), 2.17 (s, 3H), 2.80 (d, J=4.5Hz, 3H), 3.06-3.14 (m, 4H), 3.48-3.52 (m, 2H), 3.75-3.77 (m, 2H), 6.93(d, J=8.9 Hz, 2H), 7.29 (d, J=8.9 Hz, 2H), 7.46 (s, 2H), 7.90 (s, 1H),9.65 (s, 1H), 10.49 (s, 1H), 11.13 (br s, 2H). MS (ES+): m/z 437 (M+H)⁺.

Example 178N²-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(3-tert-butylphenyl)-5-methyl-pyrimidine-2,4-diamine(Compound CXIX)

A mixture of intermediate 41 (365 mg, 1.32 mmol) and4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (410 mg, 1.98 mmol) weresuspended in acetic acid (20 mL) and heated at 100° C. for 4 h. Themixture was allowed to cool to room temperature and acetic acid removedunder reduced pressure. The residue was taken in water (20 mL) andneutralized to pH˜7. The resulting solution was extracted with EtOAc (30mL) and the organic layer separated. The organic layer was washed withbrine, dried over MgSO₄ and filtered. The filtrate was concentrated invacuo and the crude product purified by HPLC to afford the titlecompound (127 mg of HCl salt, 20%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.89-1.91 (m, 2H), 1.98-2.02 (m, 2H), 2.17(s, 3H), 3.07-3.12 (m, 2H), 3.52-3.57 (m, 4H), 4.32 (t, J=4.8 Hz, 2H),6.90 (d, J=8.9 Hz, 2H), 7.29-7.38 (m, 4H), 7.43-7.44 (m, 1H), 7.48 (d,J=7.9 Hz, 1H), 7.89 (s, 1H), 9.75 (s, 1H), 10.51 (s, 1H), 11.07 (br,1H). MS (ESI+): m/z 446 (M+H)⁺.

Example 179N²-(4-(2-(Pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(4-(3-tert-butylphenylamino)-5-methylpyrimidin-2-yl)-5-methylpyrimidine-2,4-diamine(Compound CXX)

A mixture of intermediate 41 (210 mg, 0.67 mmol), intermediate 38 (185mg, 0.67 mmol), Pd₂(dba)₃ (55 mg, 0.06 mmol), Xantphos (104 mg, 0.18mmol) and cesium carbonate (782 g, 2.4 mmol) were suspended in dioxane(50 mL) and heated at reflux under the argon atmosphere for 20 h. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by HPLC to afford the title compound (94 mg of HCl salt,24%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.29 (s, 9H), 1.84-1.88 (m, 2H), 1.94-2.01(m, 2H), 2.14 (s, 3H), 2.27 (s, 3H), 3.06-3.10 (m, 2H), 3.51-3.56 (m,4H), 4.29 (t, J=4.9 Hz, 2H), 6.97 (d, J=9.1 Hz, 2H), 7.27 (d, J=8.6 Hz,2H), 7.34 (t, J=7.9 Hz, 2H), 7.57 (t, J=1.9 Hz, 2H), 7.65 (d, J=9.1 Hz,1H), 7.72 (d, J=8.6 Hz, 2H), 8.15 (s, 1H), 8.39 (s, 1H), 9.82 (s, 1H),10.21 (br s, 1H), 10.68 (br s, 1H), 10.93 (br s, 1H). MS (ES+): m/z 553(M+H)⁺.

Example 1805-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-[3-(piperidine-1-sulfony)-phenyl]-pyrimidine-2,4-diamine(Compound CXXI)

A mixture of intermediate 32 (150 mg, 0.5 mmol),1-(3-bromo-benzenesulfonyl)-piperidine (152 mg, 0.5 mmol), Pd₂(dba)₃ (46mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesium carbonate (652mg, 2 mmol) were suspended in dioxane (20 mL) and heated at reflux underthe argon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (84 mg of HCl salt, 37%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.30-1.34 (m, 2H), 1.50-1.55 (m, 4H), 2.17(s, 3H), 2.81 (d, J=4.5 Hz, 3H), 2.88 (t, J=5.3 Hz, 4H), 3.04-3.16 (m,4H), 3.47-3.51 (m, 2H), 3.75-3.77 (m, 2H), 6.33-6.34 (m, 1H), 6.95 (d,J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.56-7.63 (m, 2H), 7.83 (t, J=1.7Hz, 1H), 7.92 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 9.94 (s, 1H), 10.38 (s,1H), 10.88 (br s, 1H). MS (ES+): m/z 522 (M+H)⁺.

Example 1815-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-[3-(2-methyl-piperidine-1-sulfony)-phenyl]-pyrimidine-2,4-diamine(Compound CXXII)

A mixture of intermediate 32 (161 mg, 0.54 mmol),1-(3-bromo-benzenesulfonyl)-2-methyl-piperidine (172 mg, 0.54 mmol),Pd₂(dba)₃ (46 mg, 0.05 mmol), Xantphos (87 mg, 0.15 mmol) and cesiumcarbonate (652 mg, 2 mmol) were suspended in dioxane (20 mL) and heatedat reflux under the argon atmosphere for 20 h. The mixture was filteredand the filtrate concentrated in vacuo. The residue was purified by HPLCto afford the title compound (10 mg of HCl salt, 3%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 0.98 (d, J=6.9 Hz, 3H), 1.15-1.21 (m, 1H),1.36-1.40 (m, 3H), 1.47-1.53 (m, 2H), 2.18 (s, 3H), 2.80 (d, J=4.5 Hz,3H), 2.94-2.99 (m, 1H), 3.05-3.16 (m, 4H), 3.47-3.49 (m, 2H), 3.59-3.61(m, 2H), 3.73-3.76 (m, 2H), 4.08-4.10 (m, 1H), 6.93 (d, J=8.9 Hz, 2H),7.25 (d, J=8.9 Hz, 2H), 7.58 (t, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H),7.92 (d, J=7.1 Hz, 2H), 7.96 (br, 1H), 9.95 (s, 1H), 10.45 (s, 1H),11.00 (br s, 1H). MS (ES+): m/z 536 (M+H)⁺.

Example 182N-Cyclopentyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidine-4-ylamino}-benzenesulfonamide(Compound CXXIII)

A mixture of intermediate 32 (229 mg, 0.78 mmol),3-bromo-N-cyclopentyl-benzenesulfonamide (280 mg, 0.92 mmol), Pd₂(dba)₃(92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux underthe argon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (130 mg of HCl salt, 25%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.27-1.36 (m, 4H), 1.36-1.58 (m, 4H), 2.18(s, 3H), 2.80 (d, J=4.6 Hz, 3H), 3.05-3.15 (m, 4H), 3.36-3.42 (m, 1H),3.47-3.49 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J=8.7 Hz, 2H), 7.26 (d,J=8.9 Hz, 2H), 7.59 (t, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.75 (d,J=7.1 Hz, 2H), 7.92 (br, 2H), 7.93 (br, 1H), 9.96 (s, 1H), 10.45 (s,1H), 11.98 (br s, 1H). MS (ES+): m/z 522 (M+H)⁺.

Example 1835-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-[3-(pyrrolidine-1-sulfony)phenyl]-pyrimidine-2,4-diamine(Compound CXXIV)

A mixture of intermediate 32 (298 mg, 1.0 mmol),1-(3-bromo-benzenesulfonyl)-pyrrolidine (360 mg, 1.24 mmol), Pd₂(dba)₃(92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux underthe argon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (200 mg of HCl salt, 37%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.61-1.65 (m, 4H), 2.19 (s, 3H), 2.80 (br,3H), 3.06-3.16 (m, 10H), 3.74-3.77 (br, 2H), 6.94 (d, J=9.0 Hz, 2H),7.26 (d, J=9.0 Hz, 2H), 7.60 (t, J=8.0 Hz, 1H), 7.65 (d, J=8.0 Hz, 1H),7.91 (t, J=1.7 Hz, 1H), 7.93 (s, 1H), 8.05 (d, J=7.5 Hz, 1H), 9.95 (s,1H), 10.43 (s, 1H), 11.07 (br s, 1H). MS (ES+): m/z 508 (M+H)⁺.

Example 184N⁴-[3-(2,5-Dimethyl-pyrrolidine-1-sulfonyl)-phenyl]-5-methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Compound CXXV)

A mixture of intermediate 32 (298 mg, 1.0 mmol),1-(3-bromo-benzenesulfonyl)-2,5-dimethyl-pyrrolidine (318 mg, 1.0 mmol),Pd₂(dba)₃ (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesiumcarbonate (1.3 g, 4 mmol) were suspended in dioxane (100 mL) and heatedat reflux under the argon atmosphere for 20 h. The mixture was filteredand the filtrate concentrated in vacuo. The residue was purified by HPLCto afford the title compound (100 mg of HCl salt, 17%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.26 (s, 3H), 1.27 (s, 3H), 1.45-1.48 (m,4H), 2.19 (s, 3H), 2.80 (d, J=4.6 Hz, 3H), 3.06-3.15 (m, 4H), 3.47-3.50(m, 2H), 3.60-3.64 (m, 2H), 3.74-3.76 (m, 2H), 6.94 (d, J=9.0 Hz, 2H),7.25 (d, J=9.0 Hz, 2H), 7.59 (t, J=8.0 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H),7.93 (br, 2H), 8.02 (br, 1H), 9.97 (s, 1H), 10.47 (s, 1H), 11.07 (br s,1H). MS (ES+): m/z 536 (M+H)⁺.

Example 185N-tert-Butyl-3-[5-methyl-2-(4-piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CXXVI)

A mixture of intermediate 33 (355 mg, 1.0 mmol), tert-butyl4-(4-aminophenyl)piperazine-1-carboxylate (278 mg, 1.0 mmol), Pd₂(dba)₃(92 mg, 0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3g, 4 mmol) were suspended in dioxane (100 mL) and heated at reflux underthe argon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (10 mL) andtrifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 hat room temperature before 10% NaOH was added. The organic layer wasseparated and aqueous was extracted with CH₂Cl₂ (10 mL×2). The combinedorganic layers were dried (Na₂SO₄). The solvent was removed in vacuo.The residue was purified by HPLC to afford the title compound (62 mg,12%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.10 (s, 9H), 2.18 (s, 3H), 3.20 (br, 4H),3.33 (br, 4H), 6.94 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.57 (t,J=8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.87 (br, 1H), 7.92(br, 1H), 7.96 (br, 1H), 9.30 (br, 1H), 9.96 (s, 1H), 10.46 (s, 1H). MS(ES+): m/z 496 (M+H)⁺.

Example 186N-tert-Butyl-3-(2-{4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[5-methyl-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CXXVII)

The above-described compound CXXVI (31 mg, 0.06 mmol) was dissolved inDMF (10 mL) followed by adding 2-bromoethanol (16 mg, 0.13 mmol) anddiisopropylethylamine (33 mg, 0.25 mmol). The mixture was stirred for 48h at room temperature. Solvent was removed in vacuo and residue wasdissolved in EtOAc (20 mL). The solution was washed with saturatedNaHCO₃ and brine. The combined organic layers were dried andconcentrated until 2 mL solution followed by adding Et₂O (20 mL). Thesolid was collected by centrifugation and transferred to its HCl salt(10.7 mg, 30%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.09 (s, 9H), 2.17 (s, 3H), 3.12-3.23 (m,4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.83 (br, 2H), 4.13 (br, 2H),6.94 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H), 7.57 (t, J=8.0 Hz, 1H),7.63 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.87 (br, 1H), 7.93 (br, 1H), 7.95(br, 1H), 9.98 (s, 1H), 10.53 (s, 1H), 10.75 (br, 1H). MS (ES+): m/z 540(M+H)⁺.

Example 187N-tert-Butyl-3-[5-methyl-2-(3-piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CXXVIII)

A mixture of intermediate 33 (240 mg, 0.67 mmol), tert-butyl4-(3-aminophenyl)piperazine-1-carboxylate (166 mg, 0.6 mmol), Pd₂(dba)₃(55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate(782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated atreflux under the argon atmosphere for 20 h. The mixture was filtered andthe filtrate concentrated in vacuo. The residue was dissolved in CH₂Cl₂(10 mL) and trifuloroacetic acid (2 mL) was added. The mixture wasstirred for 4 h at room temperature before 10% NaOH was added. Theorganic layer was separated and aqueous was extracted with CH₂Cl₂ (10mL×2). The combined organic layers were dried (Na₂SO₄). The solvent wasremoved in vacuo. The residue was purified by HPLC to afford the titlecompound (18 mg, 6%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.10 (s, 9H), 2.19 (s, 3H), 3.17 (br, 4H),3.27-3.29 (m, 4H), 6.80 (d, J=8.1 Hz, 1H), 6.87 (br, 1H), 6.96 (d, J=8.1Hz, 1H), 7.16 (t, J=8.1 Hz, 1H), 7.53 (t, J=8.3 Hz, 1H), 7.61 (s, 1H),7.70 (d, J=7.8 Hz, 1H), 7.94 (br, 3H), 9.19 (br, 2H), 9.93 (s, 1H),10.48 (s, 1H). MS (ES+): m/z 496 (M+H)⁺.

Example 188N-tert-Butyl-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[5-methyl-pyrimidin-4-ylamino]-benzenesulfonamide(Compound CXXIX)

The above-described compound CXXVI (12 mg, 0.024 mmol) was dissolved inDMF (10 mL) followed by adding 2-bromoethanol (6.1 mg, 0.048 mmol) anddiisopropylethylamine (12 mg, 0.092 mmol). The mixture was stirred for48 h at room temperature. Solvent was removed in vacuo and residue wasdissolved in EtOAc (20 mL). The solution was washed with saturatedNaHCO₃ and brine. The combined organic layers were dried andconcentrated until 2 mL solution followed by adding Et₂O (20 mL). Thesolid was collected by centrifugation and transferred to its HCl salt (7mg, 51%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.09 (s, 9H), 2.19 (s, 3H), 3.12-3.22 (m,4H), 3.56-3.60 (m, 2H), 3.69-3.74 (m, 2H), 3.81 (br, 2H), 4.12 (br, 2H),6.80 (br, 1H), 6.88 (br, 1H), 6.96 (br, 1H), 7.16 (br, 1H), 7.57 (br,1H), 7.60 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.94 (br, 3H), 9.94 (s, 1H),10.49 (s, 1H). MS (ES+): m/z 540 (M+H)⁺.

Example 189N²-(4-(1H-Pyrazol-1-yl)phenyl)-N⁴-(3-tert-butylphenyl)-5-methylpyrimidine-2,4-diamine(Compound CXXX)

A mixture of intermediate 41 (580 mg, 2.1 mmol) and4-(1H-pyrazol-1-yl)benzenamine (335 mg, 2.1 mmol) were suspended inacetic acid (10 mL) and heated at 100° C. for 4 h. The mixture wasallowed to cool to room temperature and acetic acid removed underreduced pressure. The residue was taken in water (20 mL) and neutralizedto pH˜7. The resulting solution was extracted with EtOAc (30 mL) and theorganic layer separated. The organic layer was washed with brine, driedover MgSO₄ and filtered. The filtrate was concentrated in vacuo and thecrude product purified by HPLC to afford the title compound (31 mg, 4%)as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.24 (s, 9H), 2.18 (s, 3H), 6.53 (t, J=2.0Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.9 Hz, 1H), 7.44 (s, 1H),7.47 (d, J=8.2 Hz, 1H), 7.50 (d, J=8.9 Hz, 2H), 7.67 (d, J=8.9 Hz, 2H),7.73 (s, 1H), 7.95 (s, 1H), 8.43 (d, J=2.4 Hz, 1H), 9.81 (br s, 1H),10.67 (s, 1H). MS (ES+): m/z 399 (M+H)⁺.

Example 190N⁴-(7-Chloro-1H-indol-4-yl)-5-methyl-N²-(4-((piperazin-1-yl)methyl)phenyl)-pyrimidine-2,4-diamine(Compound CXXXI)

A mixture of intermediate 40 (150 mg, 0.37 mmol),4-bromo-7-chloro-1H-indole (87 mg, 0.37 mmol), Pd₂(dba)₃ (38 mg, 0.04mmol), Xantphos (76 mg, 0.12 mmol) and cesium carbonate (521 mg, 1.6mmol) were suspended in dioxane (50 mL) and heated at reflux under theargon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (10 mL) andtrifuloroacetic acid (2 mL) was added. The mixture was stirred for 4 hat room temperature before 10% NaOH was added. The organic layer wasseparated and aqueous was extracted with CH₂Cl₂ (10 mL×2). The combinedorganic layers were dried (Na₂SO₄). The solvent was removed in vacuo.The residue was purified by HPLC to afford the title compound (26 mg,15%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 2.21 (s, 3H), 3.30 (br, 4H), 3.50 (br, 4H),4.42 (br, 2H), 6.91 (s, 1H), 7.11 (d, J=8.3 Hz, 1H), 7.40 (d, J=7.5 Hz,1H), 7.42 (t, J=2.7 Hz, 1H), 7.70 (br, 4H), 8.03 (s, 1H), 9.87 (br, 1H),9.95 (s, 1H), 10.64 (s, 1H), 11.64 (s, 1H). MS (ES+): m/z 448 (M+H)⁺.

Example 191N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-pyrimidine-2,4-diamine(Compound CXXXII)

A mixture of intermediate 41 (180 mg, 0.65 mmol) and4-(2-methyl-1H-imidazol-1-yl)benzenamine (113 mg, 0.65 mmol), Pd₂(dba)₃(55 mg, 0.06 mmol), Xantphos (104 mg, 0.18 mmol) and cesium carbonate(782 mg, 2.4 mmol) were suspended in dioxane (100 mL) and heated atreflux under the argon atmosphere for 20 h. The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by HPLC toafford the title compound (78 mg of HCl salt, 27%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.26 (s, 9H), 2.21 (s, 3H), 2.50 (s, 3H),7.31-7.36 (m, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.44 (d, J=8.9 Hz, 2H), 7.47(d, J=8.0 Hz, 2H), 7.65 (d, J=8.9 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.79(d, J=2.1 Hz, 2H), 8.03 (s, 1H), 10.02 (s, 1H), 11.26 (s, 1H). MS (ES+):m/z 413 (M+H)⁺.

Example 192 4-(4-Methyl-1H-imidazol-1-yl)benzenamine (Intermediate 62)

To a solution of 1-fluoro-4-nitrobenzene (1.7 g, 12 mmol) in DMF (100mL) was added 4-methyl-1H-imidazole (0.82 g, 10 mmol) and K₂CO₃ (11 g,80 mmol). The mixture was heated at reflux under the argon atmospherefor 20 h. The mixture was filtered and the filtrate concentrated invacuo. The residue was dissolved in EtOAc (100 mL) and washed with brine(100 mL×2). The organic layer was dried and concentrated. The solid wasdissolved in MeOH and bubbled with Ar for 2 min. before adding 10% Pd—C.The hydrogenation was finished in 4 h. The catalyst was removed byfiltration and solvent was removed in vacuo to afford title compound(1.5 g, 87%) as brown solid.

Example 193N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(4-methyl-1H-imidazol-1-yl)phenyl)pyrimidine-2,4-diamine (Compound CXXXIII)

A mixture of intermediate 41 (318 mg, 1.15 mmol) and intermediate 62(200 mg, 1.15 mmol), Pd₂(dba)₃ (92 mg, 0.1 mmol), Xantphos (180 mg, 0.3mmol) and cesium carbonate (1.3 g, 4 mmol) were suspended in dioxane(100 mL) and heated at reflux under the argon atmosphere for 20 h. Themixture was filtered and the filtrate concentrated in vacuo. The residuewas purified by HPLC to afford the title compound (66 mg of HCl salt,20%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.26 (s, 9H), 2.19 (s, 3H), 2.36 (s, 3H),7.30 (d, J=7.9 Hz, 1H), 7.41 (d, J=7.9 Hz, 1H), 7.44 (t, J=1.8 Hz, 1H),7.54 (d, J=7.9 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.68 (d, J=9.0 Hz, 2H),7.94 (s, 1H), 7.99 (s, 1H), 9.53 (d, J=1.3 Hz, 1H), 9.72 (br s, 1H),10.81(br s, 1H). MS (ES+): m/z 413 (M+H)⁺.

Example 194 tert-Butyl 4-(4-aminophenyl)piperidine-1-carboxylate(Intermediate 63)

To a solution of 4-(4-nitrophenyl)piperidine (412 mg, 2 mmol) in CH2Cl2(100 mL) was added di-tert-butyl carbonate (480 mg, 2.2 mmol) andN,N-dimethylpyridin-4-amine (50 mg, 0.4 mmol). The mixture was stirredfor 20 h at room temperature. The mixture was added saturated NaHCO3(100 mL). The organic layer was separated and aqueous was extracted withCH2Cl2 (50 mL×2). The combined organic solution was dried andconcentrated in vacuo. The residue was dissolved in MeOH and bubbledwith Ar for 2 min. before adding 10% Pd—C. The hydrogenation wasfinished in 4 h. The catalyst was removed by filtration and solvent wasremoved in vacuo to afford title compound (460 mg, 83%) as white solid.

Example 195N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(piperidin-4-yl)phenyl)pyrimidine-2,4-diamine(Compound CXXXIV)

A mixture of intermediate 41 (170 mg, 0.6 mmol) and intermediate 63 (170mg, 0.6 mmol) were suspended in acetic acid (10 mL) and heated at 100°C. for 4 h. The mixture was allowed to cool to room temperature andacetic acid removed under reduced pressure. The residue was taken inwater (20 mL) and neutralized to pH˜7. The resulting solution wasextracted with EtOAc (30 mL) and the organic layer separated. Theorganic layer was washed with brine, dried over MgSO₄ and filtered. Thefiltrate was concentrated in vacuo and the crude product purified byHPLC to afford the title compound (8 mg, 3%) as a white solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.26 (s, 9H), 1.76-1.88 (m, 4H), 2.17 (s,3H), 2.76-2.81 (m, 1H), 2.93-3.00 (m, 2H), 3.36-3.40 (m, 2H), 7.07 (d,J=8.5 Hz, 1H), 7.30-7.36 (m, 4H), 7.44 (s, 1H), 7.46 (d, J=8.7 Hz, 1H),7.91 (s, 1H), 8.84 (br s, 1H), 8.92 (br s, 1H), 9.73 (s, 1H), 10.45 (s,1H). MS (ES+): m/z 416 (M+H)⁺.

Example 196N⁴-(3-tert-Butylphenyl)-5-methyl-N²-(4-(1-morpholinoethyl)phenyl)pyrimidine-2,4-diamine(Compound CXXXV)

A mixture of intermediate 41 (276 mg, 1.0 mmol) and4-(1-morpholinoethyl)benzenamine (210 mg, 1.0 mmol), Pd₂(dba)₃ (92 mg,0.1 mmol), Xantphos (180 mg, 0.3 mmol) and cesium carbonate (1.3 g, 4mmol) were suspended in dioxane (100 mL) and heated at reflux under theargon atmosphere for 20 h. The mixture was filtered and the filtrateconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound (17 mg of HCl salt, 4%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆): δ 1.26 (s, 9H), 1.66 (d, J=6.8 Hz, 3H), 2.19(s, 3H), 2.79 (br, 2H), 2.92 (br, 1H), 3.61-3.64 (m, 2H), 3.77-3.82 (m,2H), 3.94-3.99 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 7.42 (t, J=1.9 Hz, 1H),7.43 (d, J=7.8 Hz, 1H), 7.46-7.52 (m, 5H), 7.97 (s, 1H), 9.86 (s, 1H),10.78 (s, 1H), 11.72(br s, 1H). MS (ES+): m/z 446 (M+H)⁺.

Example 197 5-Bromo-2-methyl-benzenesulfonyl chloride (Intermediate 64)

Bromide (1.99 g, 11.61 mmol) was stirred vigorously and treated withchlorosulfonic acid (1.55 mL, 23.22 mmol). Once addition was complete,resulting red syrup was heated to 60° C. Reaction TLC after 10 minshowed no starting material and reaction was quenched by pouring ontoice. Product was extracted by washing with EtOAc (2×150 mL). Organicphase dried over Na₂SO₄, filtered and evaporated to yellow oil (2.2 g,70%).

Example 198 5-Bromo-2,N-dimethyl-benzenesulfonamide (Intermediate 65)

A stirring suspension of intermediate 64 (0.43 g, 1.58 mmol) in DCM (5mL) was treated with 2.0M methylamine solution in THF (2.4 mL, 4.8mmol). After 16 h reaction solvents were removed and resulting residuediluted with EtOAc (150 mL) and washed with water. Organic phase driedover Na₂SO₄, filtered and evaporated to white solids (0.37 g, 89%).

Example 1992,N-Dimethyl-5-{5-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXXXVI)

A mixture of intermediate 65 (0.14 g, 0.52 mmol), intermediate 38 (0.14g, 0.43 mmol), Pd₂(dba)₃ (0.040 g, 0.043 mmol), Xantphos (0.050 g, 0.087mmol) and cesium carbonate (0.43 g, 1.3 mmol) were suspended in dioxane(10 mL), sealed in a microwave reaction tube and irradiated withmicrowaves at 160° C. for 15 min. The reaction mixture was cooled toroom temperature and centrifuged down. The reaction was decanted and theorganic phase concentrated in vacuo. The residue was purified by HPLC toafford the title compound as a white solid (0.052 g, 24%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.66-1.70 (m, 4H), 2.08 (s, 3H), 2.43 (d,J=4.9 Hz, 3H), 2.5 (br s, 4H), 2.78, (t, J=5.7 Hz), 4.00 (t, J=5.9 Hz),6.79 (d, J=9.0 Hz, 2H), 7.31 (d, J=9.7 Hz, 1H), 7.42 (q, J=9.8 Hz, 1H),7.49 (d, J=9.0 Hz, 1H), 7.87 (s, 1H), 7.97 (d, J=2.3 Hz, 1H), 8.07-8.09(m, 1H), 8.49 (s, 1H), 8.75 (s, 1H). MS (ES+): m/z 497 (M+H)⁺.

Example 200 5-Bromo-N-tert-butyl-2-methyl-benzenesulfonamide(Intermediate 66)

A stirring suspension of intermediate 64 (1.22 g, 4.5 mmol) in DCM (25mL) was treated with tert-butylamine (1.4 mL, 13.6 mmol). After 16 h,reaction solvents were removed and resulting solids triturated withwater. Solids were dried under vacuum overnight (1.3 g, 94%).

Example 201N-tert-Butyl-5-(2-chloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-benzenesulfonamide(Intermediate 67)

A mixture of intermediate 66 (0.90 g, 2.96 mmol),2-chloro-5-methyl-pyrimidin-4-ylamine (0.33 g, 2.28 mmol), Pd₂(dba)₃(0.21 g, 0.23 mmol), Xantphos (0.264 g, 0.46 mmol) and cesium carbonate(2.2 g, 6.8 mmol) were suspended in dioxane (15 mL), sealed in amicrowave reaction tube and irradiated with microwaves at 160° C. for 15min. The reaction mixture was cooled to room temperature and centrifugeddown. The reaction was decanted and the organic phase concentrated invacuo. The residue was purified on silica gel column to afford the titlecompound as a white solid (0.12 g, 14%).

Example 202N-tert-Butyl-5-[2-(4-imidazol-1-yl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-2-methyl-benzenesulfonamide(Compound CXXXVII)

A mixture of intermediate 67 (0.113 g, 0.31 mmol),4-imidazol-1-yl-phenylamine (0.059 g, 0.37 mmol), Pd₂(dba)₃ (0.028 g,0.03 mmol), Xantphos (0.036 g, 0.06 mmol) and cesium carbonate (0.3 g,0.92 mmol) were suspended in dioxane (6 mL), sealed in a microwavereaction tube and irradiated with microwaves at 160° C. for 15 min. Thereaction was decanted and the organic phase concentrated in vacuo. Theresidue was purified by HPLC to afford the title compound as a whitesolid (0.052 g, 24%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 2.13 (s, 3H), 2.58 (s, 3H),7.07 (s, 1H), 7.34 (d, J=8.5 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H), 7.48 (s,1H), 7.60 (s, 1H), 7.78 (d, J=8.9 Hz, 2H), 7.94 (s, 1H), 7.98-8.00 (m,1H), 8.09 (s, 1H), 8.12 (d, J=2.3 Hz, 1H), 8.56 (s, 1H), 9.16 (s, 1H).MS (ES+): m/z 492 (M+H)⁺.

Example 203N-tert-Butyl-3-{5-methyl-2-[4-(pyrrolidine-1-carbonyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXXXVIII)

A mixture of intermediate 33 (0.11 g, 0.32 mmol),(4-amino-phenyl)-pyrrolidin-1-yl-methanone (0.072 g, 0.38 mmol),Pd₂(dba)₃ (0.029 g, 0.032 mmol), Xantphos (0.037 g, 0.063 mmol) andcesium carbonate (0.3 g, 0.95 mmol) were suspended in dioxane (6 mL),sealed in a microwave reaction tube and irradiated with microwaves at160° C. for 15 min. The reaction was decanted and the organic phaseconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound as a white solid (0.040 g, 25%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 1.8 (br s, 4H), 2.14 (s, 3H),3.44 (t, J=6.6 Hz, 4H), 7.38 (d, J=9.0 Hz, 2H), 7.52-7.54 (m, 2H), 7.56(s, 1H), 7.70 (d, J=9.8 Hz, 2H), 7.98 (s, 1H), 8.08-8.10 (m, 2H), 8.60(br s, 1H), 9.24 (s, 1H). MS (ES+): m/z 509 (M+H)⁺.

Example 204N-tert-Butyl-3-{5-methyl-2-[4-(morpholine-4-carbonyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXXXIX)

A mixture of intermediate 33 (0.13 g, 0.37 mmol),(4-amino-phenyl)-morpholin-4-yl-methanone (0.092 g, 0.45 mmol),Pd₂(dba)₃ (0.034 g, 0.037 mmol), Xantphos (0.043 g, 0.075 mmol) andcesium carbonate (0.37 g, 1.1 mmol) were suspended in dioxane (6 mL),sealed in a microwave reaction tube and irradiated with microwaves at160° C. for 15 min. The reaction was decanted and the organic phaseconcentrated in vacuo. The residue was purified by HPLC to afford thetitle compound as a white solid (0.065 g, 33%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 2.14 (s, 3H), 3.49 (br s,4H), 3.59 (br s, 4H), 5.75 (s, 1H), 7.25 (d, J=9.0 Hz, 2H), 7.52-7.54(m, 2H), 7.56 (s, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.98 (s, 1H), 8.06-8.08(m, 2H), 8.65 (br s, 1H), 9.26 (s, 1H). MS (ES+): m/z 525 (M+H)⁺.

Example 205N-tert-Butyl-3-{5-methyl-2-[4-(piperazine-1-carbonyl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonamide(Compound CXL)

A mixture of intermediate 33 (0.12 g, 0.33 mmol),4-(4-amino-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (0.12g, 0.45 mmol), Pd₂(dba)₃ (0.030 g, 0.037 mmol), Xantphos (0.038 g, 0.075mmol) and cesium carbonate (0.33 g, 1.1 mmol) were suspended in dioxane(6 mL), sealed in a microwave reaction tube and irradiated withmicrowaves at 160° C. for 15 min. The reaction was decanted and theorganic phase concentrated in vacuo. The residue was purified by silicagel chromatography (25%-i 00% EtOAc in Hexanes). Product was thentreated with 20 mL of 20% TFA solution in DCM. Solvents then removed byrotary evaporation. Resulting material purified by HPLC to afford thetitle compound as a white solid (0.045 g, 26%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.11 (s, 9H), 2.14 (s, 3H), 2.82 (br s,4H), 3.48 (br s, 4H), 7.24 (d, J=9.0 Hz, 2H), 7.51-7.53 (m, 2H), 7.55(s, 1H), 7.71 (d, J=9.0 Hz, 2H), 7.94 (s, 1H), 8.06-8.08 (m, 2H), 8.65(br s, 1H), 9.25 (s, 1H). MS (ES+): m/z 524 (M+H)⁺.

Example 206 tert-Butyl4-(4-(4-(3-methoxyphenylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate(Intermediate 68)

A mixture of 1-bromo-3-methoxybenzene (69.5 μL, 0.56 mmol), intermediate42 (205 mg, 0.51 mmol), Pd₂(dba)₃ (23 mg, 0.03 mmol), Xantphos (33 mg,0.06 mmol) and cesium carbonate (359 mg, 1.10 mmol) in dioxane (3 mL)was irradiated in the microwave at 160° C. for 20 min. The reactionmixture was cooled to room temperature, filtered and the filtrate rinsedwith DCM and MeOH. The combined liquids were concentrated in vacuo, andpurified using gradient flash chromatography (0-100% ethyl acetate inhexanes) to afford the title compound as a beige solid (215 mg, 83%).

Example 2073-(2-(4-(Piperidin-4-yloxy)phenylamino)-5-methylpyrimidin-4-ylamino)phenol(Compound CXLI)

To a mixture of intermediate 68 (215 mg, 0.42 mmol) in DCM (4 mL) wasadded BBr₃ (120 μL, 1.27 mmol) and stirred at room temperature for 64 h.The reaction was quenched with MeOH and concentrated in vacuo. Theresidue was purified by preparative HPLC and the fractions concentratedin vacuo to afford the TFA salt of the title compound (116 mg, 56%). TheTFA salt was taken up in MeOH and passed through SPE PL-HCO₃ MP-Resincartridges, concentrated in vacuo, triturated with ether, and filteredto provide the title compound as a white solid (31 mg, 69% recovery).

¹H NMR (500 MHz, DMSO-d₆): δ 1.51-1.60 (m, 2H), 1.90-1.98 (m, 2H), 2.07(s, 3H), 2.70-2.78 (m, 2H), 3.02-3.09 (m, 2H), 4.28-4.36 (m, 1H), 6.48(dd, J=8.1, 2.2 Hz, 1H), 6.79 (d, J=9.1 Hz, 2H), 7.06-7.11 (m, 2H), 7.16(d, J=8.5 Hz, 1H), 7.57 (d, J=9.1 Hz, 2H), 7.82 (s, 1H), 8.08 (s, 1H),8.73 (s, 1H), 9.27 (br s, 1H). MS (ES+): m/z 392 (M+H)⁺.

Example 208(2-Chloro-5-methyl-pyrimidin-4-yl)-(4-fluoro-3-methoxy-phenyl)-amine(Intermediate 69)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (1.2 g, 8.1 mmol),4-bromo-1-fluoro-2-methoxy-benzene (1.8 g, 8.9 mmol), Pd₂(dba)₃ (0.74 g,0.81 mmol), Xantphos (0.93 g, 1.6 mmol) and cesium carbonate (7.88 g,24.2 mmol) were suspended in dioxane (60 mL) and heated at reflux underthe argon atmosphere for 5 h. The reaction mixture was cooled to roomtemperature and diluted with DCM (30 mL). The mixture was filtered andthe filtrate concentrated in vacuo. The residue was purified by flashchromatography on silica gel to afford the title compound (0.3 g, 14%)as a beige solid.

Example 209N⁴-(4-Fluoro-3-methoxy-phenyl)-5-methyl-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound CXLII)

A mixture of intermediate 69 (0.1 g, 0.37 mmol) and4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.16 g, 0.75 mmol) weresuspended in acetic acid (10 mL) and heated to 110° C. for 16 h. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was purified by HPLC to afford the title compound(0.03 g, 17%) as green solids. ¹H NMR (500 MHz, DMSO-d₆): δ 1.88 (br s,2H), 2.0 (br s, 2H), 2.15 (s, 3H), 3.08 (br s, 2H), 3.55 (br s, 4H), 3.7(s, 3H), 4.32 (br s, 2H), 6.9 (d, J=7.9 Hz, 2H), 7.13 (br s, 1H),7.21-7.25 (m, 1H), 7.32-7.34 (m, 3H), 7.89 (s, 1H), 9.78 (br s, 1H),10.48 (br s, 1H), 10.92 (br s, 1H). MS (ES+): m/z 438 (M+H)⁺.

Example 210 (2-Chloro-pyrimidin-4-yl)-(3-methoxy-2-methyl-phenyl)-amine(Intermediate 70)

A mixture of 3-methoxy-2-methyl-phenylamine (0.68 g, 5 mmol) and2,4-dichloro-pyrimidine (0.74 g, 5 mmol) were suspended in ethyl alcohol(10 mL) and stirred at room temperature for 20 h. The reaction mixturewas diluted with DCM (50 mL), filtered and concentrated in vacuo. Theresidue was purified by silica gel column chromatography to afford thetitle compound (0.085 g, 7%) as yellow solids.

Example 211N⁴-(3-Methoxy-2-methyl-phenyl)-N²-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine(Compound CXLIII)

A mixture of intermediate 70 (0.08 g, 0.32 mmol) and4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (0.13 g, 0.64 mmol) weresuspended in acetic acid (10 mL) and heated to 80° C. for 16 h. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was purified by HPLC to afford the title compound(0.03 g, 17%) as grey solids.

¹H NMR (500 MHz, DMSO-d₆): δ 1.89 (br s, 2H), 2.0 (br s, 4H), 3.08 (brs, 2H), 3.4 (br s, 4H), 3.54 (br s, 4H), 3.83 (s, 3H), 4.31 (br s, 2H),6.86 (br s, 2H), 6.97 (d, J=8.1 Hz, 2H), 7.26 (t, J=8.1 Hz 1H), 7.34 (brs, 2H), 7.89 (s, 1H), 9.73 (br s, 1H), 10.62 (br s, 2H), 11.01 (br s,1H). MS (ES+): m/z 420 (M+H)⁺.

Example 212 4-(4-Acetylamino-benzenesulfonyl)-piperidine-1-carboxylicacid tert-butyl ester (Intermediate 71)

A mixture of 4-(4-bromo-benzenesulfonyl)-piperidine-1-carboxylic acidtert-butyl ester (4 g, 9.92 mmol), acetamide (0.88 g, 14.9 mmol),Pd₂(dba)₃ (0.46 g, 0.49 mmol), Xantphos (0.56 g, 0.99 mmol) and cesiumcarbonate (9.7 g, 29.8 mmol) were suspended in dioxane (60 mL) andheated at reflux under the argon atmosphere for 4 h. The reactionmixture was cooled to room temperature and poured onto ice. Resultingyellow solids collected by filtration and dried. Crude product waspurified by flash chromatography on silica gel to afford the titlecompound as a beige solid (3.12 g, 82%).

Example 213 4-(4-Amino-benzenesulfonyl)-piperidine-1-carboxylic acidtert-butyl ester (Intermediate 72)

A suspension of intermediate 71 (2.6 g, 6.7 mmol) was diluted with 60 mLof Claisen's alkali (88 g KOH dissolved in 63 mL H₂O diluted up to 250mL with MeOH) and heated to 90° C. After 2 h, reaction was removed fromheating, cooled to room temperature and diluted with water (50 mL). Greysolids collected by suction filtration, washed with water and driedovernight (2.2 g, 97%).

Example 214N⁴-(4-Chloro-3-methoxy-phenyl)-5-methyl-N²-[4-(piperidine-4-sulfonyl)-phenyl]-pyrimidine-2,4-diamine(Compound CXLIV)

A mixture of intermediate 31 (0.14 g, 0.51 mmol), intermediate 72 (0.19g, 0.56 mmol), Pd₂(dba)₃ (0.046 g, 0.051 mmol), Xantphos (0.59 g, 0.1mmol) and cesium carbonate (0.5 g, 1.52 mmol) were suspended in dioxane(8 mL) and microwaved at 160° C. for 15 min. The reaction mixture wascooled to room temperature and centrifuged down. Solvents were thendecanted and evaporated. Resulting residue was purified by flashchromatography on silica gel to afford the N-protected precursor oftitle compound. These solids were treated with 20% TFA in DCM solutionand immediately evaporated. Residue was dissolved in minimum amount toEtOAc and added dropwise to large excess of diethyl ether. Resultinglight yellow powder was collected by filtration and dried (0.16 g, 55%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.61-1.69 (m, 2H), 1.98-2.01 (m, 2H), 2.16(s, 3H), 2.86 (q, J=12 Hz, 2H), 3.35 (d, J=12.6 Hz, 2H), 3.64 (tt,J=11.7 Hz, J=3.8 Hz, 1H), 3.79 (s, 3H), 7.34 (dd, J=8.7 Hz, J=2.0 Hz,1H), 7.39-7.41 (m, 2H), 7.6 (d, J=8.9 Hz, 2H), 7.91 (d, J=8.9 Hz, 2H),8.02 (s, 1H), 8.19-8.21 (m, 1H), 8.6-8.63 (m, 1H), 8.89 (br s, 1H). MS(ES+): m/z 488 (M+H)⁺.

Example 215(4-Chloro-3-methyl-phenyl)-(2-chloro-5-methyl-pyrimidin-4-yl)-amine(Intermediate 73)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.34 g, 2.34 mmol),4-bromo-1-chloro-2-methyl-benzene (0.58 g, 2.8 ^(mmol)), Pd₂(dba)₃ (0.21g, 0.23 mmol), Xantphos (0.47 g, 0.47 mmol) and cesium carbonate (2.3 g,7 mmol) were suspended in dioxane (9 mL) microwaved at 160° C. for 20min. The reaction mixture was cooled to room temperature and centrifugeddown. Solvents were then decanted and evaporated. Resulting residue waspurified by flash chromatography on silica gel to afford title compoundas yellow solids (0.24 g, 38%).

Example 216N⁴-(4-Chloro-3-methyl-phenyl)-5-methyl-N²-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine(Compound CXLV)

A mixture of intermediate 73 (0.071 g, 0.27 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150° C.for 15 min. Solvents then removed and resulting residue purified onHPLC. Title compound isolated as white solids (0.025 g, 22%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.76-1.83 (m, 2H), 2.05-2.09 (m, 2H), 2.13(s, 3H), 2.27 (s, 3H), 3.10 (br s, 2H), 3.16 (br s, 2H), 4.58-4.61 (m,1H), 6.93 (d, J=9 Hz, 2H), 7.34-7.39 (m, 3H), 7.43-7.45 (m, 1H), 7.59(s, 1H), 7.87 (s, 1H), 8.51 (br s, 1H), 8.55 (br s, 1H), 9.38 (br s,1H), 10.0 (br s, 1H). MS (ES+): m/z 424 (M+H)⁺.

Example 217 N-(3-Bromo-phenyl)-acetamide (Intermediate 74)

A solution of 3-bromo-phenylamine (1.04 g, 6 mmol) was treated with DIEA(2.3 mL, 13.3 mmol) and chilled to zero degrees. Acetyl chloride (0.47mL, 6.7 mmol) was added dropwise via syringe. Reaction was allowed toreturn to room temperature and stir for 1 hour. Reaction was then pouredonto water and washed once. Organic phase was evaporated to beige solids(1.25 g, 98%).

Example 218N-[3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-phenyl]-acetamide(Intermediate 75)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.71 g, 4.9 mmol),intermediate 74 (1.25 g, 5.9 mmol), Pd₂(dba)₃ (0.45 g, 0.49 mmol),Xantphos (0.57 g, 0.98 mmol) and cesium carbonate (4.8 g, 14.7 mmol)were suspended in dioxane (40 mL) refluxed for 18 h. The reactionmixture was then cooled to room temperature, filtered and solventsevaporated. Resulting residue was purified by flash chromatography onsilica gel to afford title compound as white solids (0.44, 32%).

Example 219N-(3-{5-Methyl-2-[4-(piperidin-4-yloxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acetamide(Compound CXLVI)

A mixture of intermediate 75 (0.074 g, 0.27 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.1g, 0.35 mmol) were diluted with HOAc (5 mL) and microwaved at 150° C.for 15 min. Solvents then removed and resulting residue purified onHPLC. Title compound isolated as white solids (0.072 g, 62%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.74-1.81 (m, 2H), 2.03-2.07 (m, 5H), 2.15(s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.54-4.57 (m, 1H), 6.85 (d,J=8.8 Hz, 2H), 7.22 (d, J=7.7 Hz, 2H), 7.29-7.39 (m, 4H), 7.77 (s, 1H),7.87 (s, 1H), 8.55 (br s, 1H), 8.60 (br s, 1H), 9.67 (s, 1H), 10.0 (brs, 1H), 10.2 (br s, 1H). MS (ES+): m/z 433 (M+H)⁺.

Example 220 N-(3-Bromo-2-methyl-phenyl)-acetamide (Intermediate 76)

A solution of 3-bromo-2-methyl-phenylamine (4.1 g, 21.9 mmol) wastreated with DIEA (8.4 mL, 48 mmol) and chilled to zero degrees. Acetylchloride (1.7 mL, 24.1 mmol) was added dropwise via syringe. Reactionwas allowed to return to room temperature and stir for 1 hour. Reactionwas then poured onto water and washed once. Organic phase was evaporatedto off-white solids. Trituration with hexanes afforded title compound aswhite solids (4.4 g, 89%).

Example 221N-[3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-2-methyl-phenyl]-acetamide(Intermediate 77)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.86 g, 5.9 mmol),intermediate 76 (1.6 g, 7.1 mmol), Pd₂(dba)₃ (0.55 g, 0.59 mmol),Xantphos (0.69 g, 1.2 mmol) and cesium carbonate (5.8 g, 17.8 mmol) weresuspended in dioxane (40 mL) refluxed for 16 h. The reaction mixture wasthen cooled to room temperature, filtered and solvents evaporated.Resulting residue was purified by flash chromatography on silica gel toafford title compound as white solids (0.56 g, 32%).

Example 222N-(2-Methyl-3-{5-methyl-2-[4-(piperidin-4-yloxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-acetamide(Compound CXLVII)

A mixture of intermediate 77 (0.15 g, 0.5 mmol) and4-(4-Amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.19g, 0.65 mmol) were diluted with HOAc (5 mL) and microwaved at 150° C.for 15 min. Solvents then removed and resulting residue purified onHPLC. Title compound isolated as white solids (0.091 g, 41%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.71-1.78 (m, 2H), 2.02-2.08 (m, 8H), 2.16(s, 3H), 3.09 (br s, 2H), 3.24 (br s, 2H), 4.50-4.52 (m, 1H), 6.77 (d,J=8.4 Hz, 2H), 7.09-7.15 (m, 3H), 7.27 (t, J=7.9 Hz, 1H), 7.49 (d, J=8.1Hz, 1H), 7.86 (s, 1H), 8.54 (br s, 1H), 8.59 (br s, 1H), 9.45 (s, 1H),9.84 (br s, 1H), 10.34 (br s, 1H). MS (ES+): m/z 447 (M+H)⁺.

Example 2235-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-(3-nitro-phenyl)-pyrimidine-2,4-diamine(Intermediate 78)

A mixture of 1-bromo-3-nitro-benzene (0.77 g, 3.8 mmol), intermediate 32(0.95 g, 3.2 mmol), Pd₂(dba)₃ (0.29 g, 0.32 mmol), Xantphos (0.37 g,0.64 mmol) and cesium carbonate (3.1 g, 9.6 mmol) were suspended indioxane (40 mL) refluxed for 16 h. The reaction mixture was then cooledto room temperature, filtered and solvents evaporated. Resulting residuewas purified by flash chromatography on silica gel to afford titlecompound as white solids (0.53 g, 40%).

Example 224N⁴-(3-Amino-phenyl)-5-methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-pyrimidine-2,4-diamine(Intermediate 79)

Slurry of intermediate 78 (0.23 g, 0.54 mmol) in MeOH (25 mL) was purgedwith argon and treated with Pd/C 10% wt. (0.18 g). Reaction atmospherewas replaced with hydrogen and stirred for 4 h. Hydrogen balloon wasthen removed and argon was flushed through reaction before filtrationthrough Celite. Solvents were then evaporated to pale brown solids (0.17g, 83%).

Example 2251-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-3-phenyl-urea(Compound CXLVIII)

A suspension of intermediate 79 (0.17 g, 0.45 mmol) in DCM (10 mL) wastreated with phenyl isocyanate (0.058 mL, 0.54 mmol) and stirred for 1hour. Reaction solvents then removed and resulting residue purified byHPLC to provide title compound as white solids (0.075 g, 33%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.09 (s, 3H), 2.15 (s, 3H), 2.30-2.32 (m,4H), 2.92-2.94 (m, 4H), 6.74 (d, J=8.4 Hz, 2H), 6.94-6.97 (m, 1H),7.19-7.28 (m, 5H), 7.45 (d, J=8.8 Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 7.73(br s, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.68 (s, 1H), 8.74 (s, 1H), 8.78(s, 1H). MS (ES+): m/z 509 (M+H)⁺.

Example 2261-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-3-(3-trifluoromethyl-phenyl)-urea(Compound CXLIX)

A suspension of intermediate 79 (0.1 g, 0.26 mmol) in DCM (8 mL) wastreated with 1-isocyanato-3-trifluoromethyl-benzene (0.043 mL, 0.31mmol) and stirred for 1 hour. Reaction solvents then removed andresulting residue purified by HPLC to provide title compound as whitesolids (0.039 g, 26%).

¹H NMR (500 MHz, DMSO-d₆): δ 2.16 (s, 3H), 2.82 (s, 3H), 2.86 (br s,2H), 3.08 (br s, 2H), 3.42 (br s, 2H), 3.69 (br s, 2H), 6.88 (d, J=8.4Hz, 2H), 7.20 (br s, 1H), 7.29-7.33 (m, 5H), 7.52 (t, J=7.9 Hz, 1H),7.57 (d, J=8.5 Hz, 1H), 7.77 (s, 1H), 7.84 (s, 1H), 8.09 (s, 1H), 9.42(s, 1H), 9.66 (s, 1H), 9.71 (br s, 1H), 10.1 (br s, 1H). MS (ES+): m/z577 (M+H)⁺.

Example 227(2-Chloro-5-methyl-pyrimidin-4-yl)-(2-methyl-3-trifluoromethyl-phenyl)-amine(Intermediate 80)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.18 g, 5.9 mmol),1-bromo-2-methyl-3-trifluoromethyl-benzene (0.33 g, 1.4 mmol), Pd₂(dba)₃(0.12 g, 0.13 mmol), Xantphos (0.15 g, 0.25 mmol) and cesium carbonate(1.23 g, 3.8 mmol) were suspended in dioxane (8 mL) microwaved at 160°C. for 18 min. Reaction vessel was then centrifuged down and decanted.Solvents then evaporated and resulting residue was purified by flashchromatography on silica gel to afford title compound as white solids(0.095 g, 25%).

Example 2285-Methyl-N⁴-(2-methyl-3-trifluoromethyl-phenyl)-N²-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine(Compound CL)

A mixture of intermediate 80 (0.058 g, 0.2 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.073g, 0.25 mmol) were diluted with HOAc (5 mL) and microwaved at 150° C.for 15 min. Solvents then removed and resulting residue purified onHPLC. Title compound isolated as white solids (0.025 g, 30%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.71-1.78 (m, 2H), 2.00-2.04 (m, 2H), 2.18(s, 3H), 2.25 (s, 3H), 3.08 (br s, 2H), 3.22 (br s, 2H), 4.50-4.52 (m,1H), 6.70 (d, J=8.3 Hz, 2H), 7.10 (d, J=8.9 Hz, 2H), 7.54 (t, J=7.8,1H), 7.62 (d, J=7.7 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.91 (s, 1H), 8.54(br s, 1H), 8.61 (br s, 1H), 9.88 (s, 1H), 10.34 (br s, 1H). MS (ES+):m/z 458 (M+H)⁺.

Example 229 (3-Bromo-phenyl)-pyrrolidin-1-yl-methanone (Intermediate 81)

A solution of 3-bromo-benzoyl chloride (2.7 g, 12 mmol) in DCM (40 mL)was chilled to zero degrees and treated with pyrrolidine (3 mL, 36.8mmol). Reaction was allowed to come to room temperature and stir for 4h. Mixture was then poured onto water and washed once. Organic phasethen washed with brine, dried over sodium sulfate, filtered andevaporated to amber oil (3.1 g, 100%).

Example 230[3-(2-Chloro-5-methyl-pyrimidin-4-ylamino)-phenyl]-pyrrolidin-1-yl-methanone(Intermediate 82)

A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.22 g, 1.5 mmol),intermediate 81 (0.46 g, 1.8 mmol), Pd₂(dba)₃ (0.14 g, 0.15 mmol),Xantphos (0.17 g, 0.3 mmol) and cesium carbonate (1.5 g, 4.5 mmol) weresuspended in dioxane (8 mL) microwaved at 160° C. for 18 min. Reactionvessel was then centrifuged down and decanted. Solvents then evaporatedand resulting residue was purified by flash chromatography on silica gelto afford title compound as white solids (0.25 g, 53%).

Example 231(3-{5-Methyl-2-[4-(piperidin-4-yloxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-pyrrolidin-1-yl-methanone(Compound CLI)

A mixture of intermediate 82 (0.1 g, 0.32 mmol) and4-(4-amino-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (0.12g, 0.41 mmol) were diluted with HOAc (6 mL) and microwaved at 150° C.for 15 min. Solvents then removed and resulting residue purified onHPLC. Title compound isolated as white solids (0.005 g, 3%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.74-1.81 (m, 4H), 1.83-1.88 (m, 2H),2.05-2.09 (m, 2H), 2.16 (s, 3H), 2.25 (s, 3H), 3.25 (br s, 2H), 3.34 (t,J=6.5 Hz, 2H), 3.46 (t, J=6.9 Hz, 2H), 4.45-4.59 (m, 1H), 6.91 (d, J=8.8Hz, 2H), 7.32 (d, J=8.9 Hz, 2H), 7.36 (d, J=7.7 Hz, 1H), 7.43 (t, J=7.8,1H), 7.67 (d, J=7.9 Hz, 1H), 7.70 (s, 1H), 7.89 (s, 1H), 8.50 (br s,1H), 8.56 (br s, 1H), 9.64 (br s, 1H), 10.21 (br s, 1H). MS (ES+): m/z473 (M+H)⁺.

Example 232 3-Bromo-N-isopropyl-benzamide (Intermediate 83)

A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (40 mL)was chilled to zero degrees and treated with isopropylamine (0.96 mL,11.32 mmol). Reaction was allowed to come to room temperature and stirfor 24 h. Mixture was then poured onto water and washed once. Organicphase then washed with brine, dried over sodium sulfate, filtered andevaporated to white solids (0.6 g, 66%).

Example 233N-Isopropyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzamide(Compound CLII)

A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 83 (0.13g, 0.54 mmol), Pd₂(dba)₃ (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8mL) microwaved at 160° C. for 15 min. Reaction vessel was thencentrifuged down and decanted. Solvents then evaporated and resultingresidue was purified by HPLC to afford title compound as white solids(0.011 g, 7%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.14 (d, J=6.7 Hz, 6H), 2.16 (s, 4H), 2.87(s, 4H), 3.10 (br s, 2H), 3.51 (s, 2H), 4.22 (m, 1H), 6.85 (d, J=8.8 Hz,2H), 7.30-7.32 (m, 2H), 7.45 (t, J=7.8 Hz, 1H), 7.69-7.70 (m, 2H), 7.90(s, 1H), 7.99 (s, 1H), 8.24 (d, J=7.7 Hz, 1H), 9.70 (br s, 1H), 9.94 (brs, 1H), 10.2 (br s, 1H). MS (ES+): m/z 460 (M+H)⁺.

Example 234 3-Bromo-N-tert-butyl-benzamide (Intermediate 84)

A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (10 mL)was chilled to zero degrees and treated with tert-butylamine (1.2 mL,11.3 mmol). Reaction was allowed to come to room temperature and stirfor 4 h. Mixture was then poured onto water and washed once. Organicphase then washed with brine, dried over sodium sulfate, filtered andevaporated to amber oil (0.9 g, 94%).

Example 235N-tert-Butyl-3-{5-methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzamide(Compound CLIII)

A mixture of intermediate 32 (0.1 g, 0.34 mmol), intermediate 84 (0.1 g,0.4 mmol), Pd₂(dba)₃ (0.031 g, 0.034 mmol), Xantphos (0.039 g, 0.067mmol) and cesium carbonate (0.33 g, 1 mmol) were suspended in dioxane (8mL) microwaved at 160° C. for 15 min. Reaction vessel was thencentrifuged down and decanted. Solvents then evaporated and resultingresidue was purified by HPLC to afford title compound as white solids(0.055 g, 35%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.36 (s, 9H), 2.09 (s, 3H), 2.21 (s, 3H),2.43 (t, J=2.8 Hz, 4H), 3.00 (t, J=2.8 Hz, 4H), 6.74 (d, J=9.1 Hz, 2H),7.35 (t, J=7.9 Hz, 1H), 7.44-7.48 (m, 3H), 7.67 (s, 1H), 7.85 (s, 1H),7.88-7.92 (m, 2H), 8.36 (s, 1H), 8.74 (s, 1H). MS (ES+): m/z 474 (M+H)⁺.

Example 2365-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-(3-piperidin-4-yl-phenyl)-pyrimidine-2,4-diamine(Compound CLIV)

A mixture of intermediate 32 (0.08 g, 0.27 mmol),4-(3-bromo-phenyl)-piperidine (0.084 g, 0.35 mmol), Pd₂(dba)₃ (0.025 g,0.027 mmol), Xantphos (0.031 g, 0.054 mmol) and cesium carbonate (0.26g, 0.81 mmol) were suspended in dioxane (8 mL) microwaved at 160° C. for15 min. Reaction vessel was then centrifuged down and decanted. Solventsthen evaporated and resulting residue was purified by HPLC to affordtitle compound as white solids (0.007 g, 6%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.74-1.79 (m, 3H), 2.09 (s, 3H), 2.21 (s,3H), 2.43 (t, J=2.8 Hz, 4H), 3.00 (t, J=2.8 Hz, 4H), 6.76 (d, J=9.1 Hz,2H), 6.90 (d, J=7.7 Hz, 1H), 7.24 (t, J=7.9 Hz, 1H), 7.47-7.53 (m, 3H),7.68 (d, J=8.2 Hz, 1H), 7.82 (s, 1H), 8.18 (s, 1H), 8.67 (s, 1H). MS(ES+): m/z 458 (M+H)⁺.

Example 2374-(3-{5-Methyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzenesulfonyl)-piperidine-1-carboxylicacid benzyl ester (Intermediate 85)

A mixture of intermediate 32 (0.17 g, 0.58 mmol),4-(3-bromo-benzenesulfonyl)-piperidine-1-carboxylic acid benzyl ester(0.28 g, 0.64 mmol), Pd₂(dba)₃ (0.053 g, 0.058 mmol), Xantphos (0.067 g,0.12 mmol) and cesium carbonate (0.57 g, 1.74 mmol) were suspended indioxane (8 mL) microwaved at 160° C. for 15 min. Reaction vessel wasthen centrifuged down and decanted onto ice. Yellow solids collected,dried and used without further purification (0.4 g, 100%).

Example 2385-Methyl-N²-[4-(4-methyl-piperazin-1-yl)-phenyl]-N⁴-[3-(piperidine-4-sulfonyl)-phenyl]-pyrimidine-2,4-diamine(Compound CLV)

A stirring solution of intermediate 85 (0.17 g, 0.26 mmol) in DCM (15mL) was treated with 1M BBr₃ in DCM (2 mL, 2 mmol). After 4 h, reactionwas quenched by slow addition of MeOH (4 mL) followed by removal ofsolvents. Residue purified by HPLC to provide title compound as purplepowder (0.008 g, 6%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.31-1.40 (m, 2H), 1.75 (d, J=10.8 Hz, 2H),2.12 (s, 3H), 2.21 (s, 3H), 2.36-2.41 (m, 2H), 2.44 (t, J=4.9 Hz, 4H),2.95 (d, J=12.5 Hz, 2H), 3.02 (t, J=4.9 Hz, 4H), 3.24 (tt, J=11.7 Hz,J=3.8 Hz, 1H), 6.81 (d, J=9.0 Hz, 2H), 7.44 (m, 3H), 7.56 (t, J=8.0 Hz,1H), 7.90-7.91 (m, 2H), 8.49 (d, J=7.6 Hz, 1H), 8.60 (s, 1H), 8.74 (s,1H). MS (ES+): m/z 522 (M+H)⁺.

Example 239 tert-Butyl4-(4-(4-(1H-indol-4-ylamino)-5-methylpyrimidin-2-ylamino)phenoxy)piperidine-1-carboxylate(Intermediate 86)

A mixture of 4-bromo-1H-indole (41 μL, 0.33 mmol), intermediate 42 (131mg, 0.33 mmol), Pd₂(dba)₃ (30 mg, 0.03 mmol), Xantphos (60 mg, 0.10mmol) and cesium carbonate (428 mg, 1.31 mmol) in dioxane (3 mL) wasirradiated in the microwaved at 160° C. for 20 min. The reaction mixturewas cooled to room temperature and filtered rinsing with DCM. Thefiltrate was concentrated and purified by gradient flash chromatography(0-15% MeOH in DCM) to afford the title compound as a white solid (30mg, 17%).

Example 240N⁴-(1H-Indol-4-yl)-5-methyl-N²-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4-diamine(Compound CLVI)

A mixture of intermediate 86 (27 mg, 0.05 mmol) in 30% TFA/DCM (1 mL)was stirred for 3 h. The reaction mixture was concentrated in vacuo andpurified by preparative HPLC. The resulting fractions were concentratedin vacuo to obtain the TFA salt of the title compound as a tan solid (11mg, 43%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.71-1.77 (m, 2H), 1.98-2.06 (m, 2H), 2.22(s, 3H), 3.03-3.12 (m, 2H), 3.19-3.27 (m, 2H), 4.44-4.53 (m, 1H),6.34-6.37 (m, 1H), 6.64 (br d, J=8.3 Hz, 2H), 7.08 (t, J=7.2 Hz, 3H),7.14 (t, J=7.8 Hz, 1H), 7.36 (t, J=2.7 Hz, 1H), 7.39 (d, J=8.1 Hz, 1H),7.84 (s, 1H), 8.48 (br s, 1H), 8.55 (br s, 1H), 9.85 (br s, 1H), 9.98(br s, 1H), 11.27 (s, 1H).

Example 2412-Chloro-N-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-5-yl}-5(3-trifluoromethyl-benzoylamino)-benzamide(Compound CLVII)

A mixture of 3-bromopyridine (379 mg, 2.4 mmol),4-amino-2-chloro-5-methylpyrimidine (287 mg, 2.0 mmol), Pd₂(dba)₃ (18mg, 0.02 mmol), xantphos (23 mg, 0.04 mmol) and cesium carbonate (975mg, 3.0 mmol) in dioxane (15 mL) was heated under refluxed for 1 h underargon. The solvent was removed and the residue on purification by HPLCgave an intermediate,2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as yellow solid (252mg, 57%). For second Buckwald, a mixture of2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine (80 mg, 0.36 mmol),4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (74 mg, 0.34 mmol), Pd₂(dba)₃(3.2 mg, 0.003 mmol), xantphos (4.2 mg, 0.007 mmol) and cesium carbonate(234 mg, 0.72 mmol) in dioxane (5 mL) was heated under refluxed for 1 hunder argon. The crude reaction mixture on purification using HPLC gavethe title compound as light brown solid (28 mg, 20%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.85-1.95 (m, 2H), 2.0-2.09 (m, 2H), 2.18(s, 3H), 3.09-3.18 (m, 2H), 3.55-3.65 (m, 4H), 4.27 (dd, J=5.2, 4.7 Hz,2H), 6.94 (d, J=8.9 Hz, 2H), 7.35 (d, J=8.9 Hz, 2H), 7.50 (dd, J=8.2,4.8 Hz, 1H), 7.92-7.96 (m, 1H), 8.08-8.15 (m, 1H), 8.45 (dd, J=4.8, 1.4,1H), 8.84, 9.75, 9.85, 10.24 (4 br s, 1H each). MS (ES+): m/z 329(M+H)⁺.

Example 242N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-5-methyl-N⁴-(3-(trifluoromethoxy)phenyl)pyrimidine-2,4-diamine(Compound CLVIII)

A mixture of 1-bromo-3-(trifluoromethoxy)benzene (241 mg, 1.0 mmol),4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd₂(dba)₃ (9 mg,0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650 mg,2.0 mmol) in dioxane (15 mL) was heated under refluxed for 10 h underargon. The solvent was removed and the residue on purification by HPLCgave an intermediate,2-chloro-5-methyl-N-(pyridin-3-yl)pyrimidin-4-amine as brown solid (260mg, 85%). A mixture of this intermediate (100 mg, 0.33 mmol) and4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (67 mg, 0.33 mmol) in glacialacetic acid (5 mL) was heated under refluxed for 3 h under argon. Thecrude reaction mixture on purification using HPLC gave the titlecompound as white solid (11 mg, 7%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.72 (m, 4H), 2.11 (s, 3H), 2.51-2.55(m, 2H, superimposed with solvent peak), 2.75 (t, J=5.9 Hz, 2H),3.25-3.34 (m, 2H, superimposed with water peak), 3.99 (t, J=5.9 Hz, 2H),6.79 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.6, 7.4 Hz,1H), 7.50 (d, J=8.9 Hz, 2H), 7.76 (br s, 1H), 7.87 (d, J=8.4 1H), 7.90,8.31, 8.41, 8.84 (4 s, 1H each). MS (ES+): m/z 474 (M+H)⁺.

Example 243N²-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-N⁴-(4-chloro-3-(trifluoromethyl)phenyl)-5-methylpyrimidine-2,4-diamine(Compound CLIX)

A mixture of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (259 mg, 1.0mmol), 4-amino-2-chloro-5-methylpyrimidine (143 mg, 1.0 mmol), Pd₂(dba)₃(9 mg, 0.01 mmol), xantphos (14 mg, 0.02 mmol) and cesium carbonate (650mg, 2.0 mmol) in dioxane (15 mL) was heated under refluxed for 10 hunder argon. The solvent was removed and the residue was purified byHPLC to give an intermediate2-chloro-N-(4-chloro-3-(trifluoromethyl)phenyl)-5-methylpyrimidin-4-amineas brown solid (200 mg, 62%). A mixture of this intermediate (161 mg,0.5 mmol) and 4-(2-(pyrrolidin-1-yl)ethoxy)benzenamine (103 mg, 0.5mmol) in glacial acetic acid (5 mL) was heated under refluxed for 3 hunder argon. The crude reaction mixture on purification using HPLC gavethe title compound as brown solid (75 mg, 31%).

¹H NMR (500 MHz, DMSO-d₆): δ 1.65-1.72 (m, 4H), 2.10 (s, 3H), 2.51-2.55(m, 4H, superimposed with solvent peak), 2.75 (t, J=6.0 Hz, 2H), 4.0 (t,J=5.9 Hz, 2H), 6.79 (d, J=8.5 Hz, 2H), 7.47 (d, J=9.0 Hz, 2H), 7.58 (d,J=9.0 Hz, 2H), 7.93 (s, 1H), 8.01 (d, J=2.5 Hz, 1H), 8.22 (d, J=8.5 Hz,2H), 8.60, 8.88 (2 s, 1H each). MS (ES+): m/z 492 (M+H)⁺.

Example 244 IC₅₀ Value Determinations for Jak2 Kinase

The IC₅₀ values for compounds were determined using a luminescence-basedkinase assay with recombinant JAK2 obtained from Upstate Cell SignalingSolutions. In white, flat-bottom, 96-well plates (Nunc) parallel assayswere run at room temperature at a final volume of 50 μL. Each wellcontained 40 μL of buffer consisting of 40 mM Tris buffer, pH 7.4,containing 50 mM MgCl₂, 800 μM EGTA, 350 μM Triton X-100, 2 mMβ-mercaptoethanol, 100 μM peptide substrate (PDKtide; Upstate CellSignaling Solutions) and an appropriate amount of JAK2 (75-25 ng/well)such that the assay was linear over 60 min. The final concentrations ofTargeGen compounds for IC₅₀ value determinations ranged from 1000 to0.01 μM by adding the appropriate amount of compound in 2.5 μL of DMSO;the DMSO present in each assay was constant at 5%. The reaction wasinitiated by the addition of 10 μL of ATP to a final assay concentrationof 3 μM. After the reaction had proceeded for 60 min, 50 μL ofKinase-Glo reagent (Promega) was added to terminate the reaction. Thissolution was then allowed to proceed for an additional 10 min tomaximize the luminescence reaction.

Values were then measured using an Ultra 384 instrument (Tecan) set forluminosity measurements. Two control reactions were also ran: onereaction containing no compound and the second containing neitherinhibitor nor peptide substrate. IC₅₀ values were derived fromexperimental data using the non-linear curve fitting capabilities ofPrism (Version 4; GraphPad Software). The results are shown in Table 1.TABLE 1 Compounds of the Invention And Their IC Values for Jak2 KinaseJAK2 Structure Name IC50

4-(2,4-Dichloro-5-methoxy- phenylamino)-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]- pyrimidine-5-carbonitrile 6240

4-(2,4-Dichloro-5-methoxy- phenylamino)-2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]- pyrimidine-5-carbonitrile 10500

N4-(2,4-Dichloro-5-methoxy- phenyl)-5-methyl-N2-[3-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- pyrimidine-2,4-diamine 2040

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(3- methoxyphenyl)-5-methylpyrimidine-2,4-diamine Hydrochloride 52.8

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-methyl-N4-(3-nitrophenyl)pyrimidine-2,4- diamine Hydrochloride 61.1

N4-(4-Methoxy-phenyl)-N2-[4- (2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine trifluoroacetate 4330

4-[4-(4-Methoxy-phenylamino)- pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)- benzenesulfonamide trifluoroacetate 10700

4-[4-(3-Methoxy-phenylamino)- pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)- benzenesulfonamide trifluoroacetate 638

N4-Benzo[1,3]dioxol-5-yl-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine trifluoroacetate 87.2

4-[4-(4-Hydroxy-phenylamino)- pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)- benzenesulfonamide 9740

3-(2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenylamino)-5- methylpyrimidin-4-ylamino)phenol Hydrochloride 203

4-[4-(3-Hydroxy-phenylamino)- pyrimidin-2-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)- benzenesulfonamide trifluoroacetate 3620

N-Methyl-3-{5-methyl-2-[4-(2- pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4- ylamino}-benzamide 257

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- pyrimidine-2,4-diamine 7.96

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4- (isoquinolin-1-yl)-5-methylpyrimidine-2,4-diamine 1050

N4-(3-Dimethylamino-phenyl)-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 19.7

4-(2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenylamino)-5-methylpyrimidin-4-ylamino)-2- chlorobenzonitrile Hydrochloride 67.5

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-methyl-N4-(naphthalen-1-yl)pyrimidine-2,4- diamine Hydrochloride 20

N4-(3,4-Dichloro-phenyl)-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 25.7

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(3-piperazin-1-ylmethyl-phenyl)- pyrimidine-2,4-diamine 15.8

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(1H-indol-4-yl)-5-methylpyrimidine-2,4- diamine Hydrochloride 19.2

N-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-4- benzylpyrimidin-2-amine702.000000

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(4-chloro-3-methoxyphenyl)-N4,5- dimethylpyrimidine-2,4-diamine trifluoroacetate4900

N4-(4-Chloro-phenyl)-5-methyl- N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine trifluoroacetate 18.2

2-{4-[4-(4-Chloro-3-methoxy- phenylamino)-5-methyl-pyrimidin-2-ylamino]-phenoxy}- ethanol 9.14

5-Methyl-N4-phenyl-N2-[4-(2- pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine 16.7

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-methyl-N4-p-tolylpyrimidine-2,4-diamine Hydrochloride 35.7

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(4-chloro-3-methylphenyl)-5- methylpyrimidine-2,4-diamine Hydrochloride 12.4

N4-(4-Chloro-3-fluoro-phenyl)- 5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine- 2,4-diamine 40.1

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4-morpholin-4-ylmethyl-phenyl)- pyrimidine-2,4-diamine trifluoroacetate13.3

N4-Benzo[b]thiophen-5-yl-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 28.5

N4-Benzo[b]thiophen-3-yl-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 12.4

N4-(3-Chloro-phenyl)-5-methyl- N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4-diamine 20.8

2-Chloro-N-{2-[4-(2-pyrrolidin- 1-yl-ethoxy)-phenylamino]-pyrimidin-5-yl}-5-(3- trifluoromethyl-benzoylamino)- benzamide 304

N4-(4-Fluoro-3-methoxy- phenyl)-5-methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]- pyrimidine-2,4-diamine 14.8

N4-Benzo[1,3]dioxol-4-yl-5- methyl-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 16.9

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(3- piperazin-1-yl-phenyl)-pyrimidine-2,4-diamine 9.52

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(3-(trifluoromethyl)phenyl)-5- methylpyrimidine-2,4-diamine 17.6

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(4-(trifluoromethyl)phenyl)-5- methylpyrimidine-2,4-diamine hydrochloride39.8

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4-pyrazol-1-ylmethyl-phenyl)-pyrimidine- 2,4-diamine 18.9

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-methyl-N4- (3-(trifluoromethoxy)phenyl)- pyrimidine-2,4-diamine 20.7

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(4-chloro-3-(trifluoromethyl)phenyl)-5- methylpyrimidine-2,4-diamine 23.4

N4-(3-Methoxy-2-methyl- phenyl)-N2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-pyrimidine-2,4- diamine 371

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-[4-(piperidine-4-sulfonyl)-phenyl]- pyrimidine-2,4-diamine 13

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-[4-(4-methyl-piperazin-1-yl)-phenyl]- pyrimidine-2,4-diamine 5.5

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4- morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine 130

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4-pyrazol-1-yl-phenyl)-pyrimidine-2,4- diamine trifluoroacetate 35.3

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4- piperidin-1-yl-phenyl)-pyrimidine-2,4-diamine 35.3

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-[4-(4-methyl-piperazin-1-ylmethyl)- phenyl]-pyrimidine-2,4-diamine 12

N4-(1H-indol-4-yl)-5-methyl- N2-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 9.53

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4- piperazin-1-yl-phenyl)-pyrimidine-2,4-diamine 6.15

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-[4-(piperidin-4-yloxy)-phenyl]- pyrimidine-2,4-diamine 4.14

3-{5-Methyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-benzamide 23

3-{5-Methyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}- benzenesulfonamide 13.6

N4-(4-Chloro-3-methyl-phenyl)- 5-methyl-N2-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4- diamine 8.41

N-(3-{5-Methyl-2-[4-(piperidin- 4-yloxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)- acetamide 137

N4-Benzo[1,3]dioxol-4-yl-5- methyl-N2-[4-(4-methyl-piperazin-1-yl)-phenyl]- pyrimidine-2,4-diamine 14.2

N4-(4-Chloro-3-trifluoromethyl- phenyl)-5-methyl-N2-[4-(piperidin-4-yloxy)-phenyl]- pyrimidine-2,4-diamine 11.4

N4-(7-chloro-1H-indol-4-yl)-5- methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine 5.36

N-(2-Methyl-3-{5-methyl-2-[4- (piperidin-4-yloxy)-phenylamino]-pyrimidin-4- ylamino}-phenyl)-acetamide 146

5-methyl-N4-(2,3- dimethylphenyl)-N2-(4- (piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine Hydrochloride 4.38

5-methyl-N4-(3,5- dimethylphenyl)-N2-(4- (piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine hydrochloride 37.2

1-(3-{5-Methyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-3- phenyl-urea 63.6

N4-(4-chloro-3,5- dimethylphenyl)-5-methyl-N2- (4-(4-methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 38

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 4.7

N-Methyl-3-{5-methyl-2-[4-(4- methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 16.1

N,N-Dimethyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 9.5

5-methyl-N4-(7-methyl-1H- indol-4-yl)-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 3.84

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine Hydrochloride 2.73

N4-(3,5-dimethoxyphenyl)-5- methyl-N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine trifluoroacetate 137

1-(3-{5-Methyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-3- (3-trifluoromethyl-phenyl)-urea 126

2-Methyl-3-{5-methyl-2-[4-(4- methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzoic acid ethyl ester 27.8

2-Methyl-3-{5-methyl-2-[4-(4- methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzamide 26.2

N4-(1H-indol-4-yl)-5-methyl- N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine trifluoroacetic acid salt 4.27

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(3-tert- butylphenyl)-5-methylpyrimidine-2,4-diamine Hydrochloride 6.71

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(4-(3-tert-butylphenylamino)-5- methylpyrimidin-2-yl)-5-methylpyrimidine-2,4-diamine Hydrochloride 153

5-Methyl-N4-(2-methyl-3- trifluoromethyl-phenyl)-N2-[4-(piperidin-4-yloxy)-phenyl]- pyrimidine-2,4-diamine 52.9

3-{5-Methyl-2-[4-(2-pyrrolidin- 1-yl-ethoxy)-phenylamino]-pyrimidin-4-ylamino}- benzenesulfonamide 72.2

N-Isopropyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 11.8

N-tert-Butyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 6.06

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-[3-(piperidine-1-sulfony)-phenyl]- pyrimidine-2,4-diamine Hydrochloride24.8

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-[3-(2-methyl-piperidine-1-sulfony)- phenyl]-pyrimidine-2,4-diamineHydrochloride 33.5

N4-(3-Methanesulfonyl-4- methyl-phenyl)-5-methyl-N2-[4-(4-methyl-piperazin-1-yl)- phenyl]-pyrimidine-2,4-diamine 160

N-Cyclohexyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 39.4

N,N-Diethyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 60.3

N4-(3-(trifluoromethyl)-2- methylphenyl)-5-methyl-N2-(4-(4-methylpiperazin-1- yl)phenyl)pyrimidine-2,4- diamine hydrochloride87.1

(3-{5-Methyl-2-[4-(piperidin-4- yloxy)-phenylamino]-pyrimidin-4-ylamino}-phenyl)-pyrrolidin-1- yl-methanone 113

N-Cyclopentyl3-{5-Methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidine-4- ylamino}-benzenesulfonamide Hydrochloride19.8

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-[3-(pyrrolidine-1-sulfony)-phenyl]- pyrimidine-2,4-diamine Hydrochloride17.1

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-[3-(morpholine-4-sulfonyl)-phenyl]- pyrimidine-2,4-diamine 20.7

N-Isopropyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzamide 541

5-methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)- N4-(3-(methylsulfonyl)phenyl)- pyrimidine-2,4-diamine 215

N-tert-Butyl-3-{5-methyl-2-[4- (4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzamide 890

5-methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)- N4-(3-(propylsulfonyl)phenyl)- pyrimidine-2,4-diamine 8

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-(3-piperidin-4-yl-phenyl)- pyrimidine-2,4-diamine 42.5

N-tert-Butyl-3-[5-methyl-2-(4- morpholin-4-ylmethyl-phenylamino)-pyrimidin-4- ylamino]-benzenesulfonamide 12.5

N-tert-Butyl-3-[5-methyl-2-(4- piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]- benzenesulfonamide Hydrochloride 7.59

N4-[3-(2,5-Dimethyl-pyrrolidine- 1-sulfonyl)-phenyl]-5-methyl-N2-[4-(4-methyl-piperazin-1-yl)- phenyl]-pyrimidine-2,4-diamineHydrochloride 18.8

N-tert-Butyl-3-(2-{4-[4-(2- hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[5-methyl- pyrimidin-4-ylamino]- benzenesulfonamideHydrochloride 7.09

N-tert-Butyl-3-[5-methyl-2-(4- pyrazol-1-yl-phenylamino)-pyrimidin-4-ylamino]- benzenesulfonamide 19

N-tert-Butyl-3-[5-methyl-2-(6- piperazin-1-yl-pyridin-3-ylamino)-pyrimidin-4-ylamino]- benzenesulfonamide 10

2-[4-(3-{5-Methyl-2-[4-(4- methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4- ylamino}-phenyl)-piperidin-1- yl]-ethanol 8.46

N-tert-Butyl-3-[5-methyl-2-(3- morpholin-4-ylmethyl-phenylamino)-pyrimidin-4- ylamino]-benzenesulfonamide 7.06

N-tert-Butyl-3-[5-methyl-2-(4- pyrazol-1-ylmethyl-phenylamino)-pyrimidin-4- ylamino}-benzenesulfonamide 18.6

N-tert-Butyl-3-{5-methyl-2-[3- (piperidine-1-sulfonyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 316

N-tert-butyl-3-{[5-methyl-2-({4- [(4-methylpiperazin-1-yl)methyl]phenyl}amino)- pyrimidin-4- yl]amino}benzenesulfonamide 29.8

N-tert-butyl-3-[(5-methyl-2-{[4- piperazin-1-yl-3-(trifluoromethyl)phenyl]amino}- pyrimidin-4- yl)amino]benzenesulfonamide22.5

3-[(2-{[4-(4-acetylpiperazin-1- yl)-3- (trifluoromethyl)phenyl]amino}-5-methylpyrimidin-4-yl)amino]- N-tert-butylbenzenesulfonamide 35.7

N-tert-Butyl-3-[5-methyl-2-(3- piperazin-1-yl-phenylamino)-pyrimidin-4-ylamino]- benzenesulfonamide Hydrochloride 18

N-tert-Butyl-3-(2-{3-[4-(2- hydroxy-ethyl)-piperazin-1-yl]-phenylamino}-[5-methyl- pyrimidin-4-ylamino]- benzenesulfonamideHydrochloride 40.5

N-tert-butyl-3-{[5-methyl-2-({3- [(4-methylpiperazin-1-yl)sulfonyl]phenyl}amino)- pyrimidin-4- yl]amino}benzenesulfonamide 650

N-tert-butyl-3-[(5-methyl-2-{[4- (piperazin-1- ylmethyl)phenyl]amino}-pyrimidin-4- yl)amino]benzenesulfonamide 4.6

5-Methyl-N2-[4-(4-methyl- piperazin-1-yl)-phenyl]-N4-[3-(piperidine-4-sulfonyl)-phenyl]- pyrimidine-2,4-diamine 198

5-methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)- N4-(3-(piperidin-1-yl)phenyl)pyrimidine-2,4- diamine 46.3

N4-(3-(1H-pyrrol-1-yl)phenyl)-5- methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine 33.8

3-{5-Methyl-2-[4-(4-methyl- piperazin-1-yl)-phenylamino]-pyrimidin-4-ylamino}-N- piperidin-4-yl- benzenesulfonamide 543

N4-(1H-indazol-4-yl)-5-methyl- N2-(4-(piperidin-4-yloxy)phenyl)pyrimidine-2,4- diamine Hydrochloride

N4-(1H-Indol-4-yl)-5-methyl- N2-(4-morpholin-4-ylmethyl-phenyl)-pyrimidine-2,4-diamine 7.42

N4-(1H-Indol-4-yl)-5-methyl- N2-(4-piperazin-1-ylmethyl-phenyl)-pyrimidine-2,4-diamine 10.1

N-tert-Butyl-3-{5-methyl-2-[4- (2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 12.5

3-(2-(4-(piperidin-4- yloxy)phenylamino)-5- methylpyrimidin-4-ylamino)phenol 51.9

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(7-chloro-1H-indol-4-yl)-5- methylpyrimidine-2,4-diamine Hydrochloride 1.16

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-5-methyl-N4-(7-methyl-1H-indol-4- yl)pyrimidine-2,4-diamine Hydrochloride 6.98

N2-(4-(2-(pyrrolidin-1- yl)ethoxy)phenyl)-N4-(7-fluoro-1H-indol-4-yl)-5- methylpyrimidine-2,4-diamine Hydrochloride 9.28

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(6-piperazin-1-yl-pyridin-3-yl)- pyrimidine-2,4-diamine 12.1

5-[4-(4-Chloro-3-methoxy- phenylamino)-5-methyl- pyrimidin-2-ylamino]-2-piperazin-1-yl-benzoic acid methyl ester 5.12

5-[4-(Benzo[1,3]dioxol-4- ylamino)-5-methyl-pyrimidin-2-ylamino]-2-(2-pyrrolidin-1-yl- ethoxy)-benzoic acid methyl ester 16.4

N-tert-Butyl-3-{5-methyl-2-[4- (piperidin-4-yloxy)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 7.3

N4-(1H-Indol-5-yl)-5-methyl- N2-[4-(piperidin-4-yloxy)-phenyl]-pyrimidine-2,4-diamine

2-{5-[4-(Benzo[1,3]dioxol-4- ylamino)-5-methyl-pyrimidin-2-ylamino]-pyridin-2-yloxy}- ethanol 116

N4-Benzo[1,3]dioxol-4-yl-N2-[3- methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-methyl- pyrimidine-2,4-diamine 9.34

N-tert-Butyl-3-[2-(4-imidazol-1- yl-phenylamino)-5-methyl-pyrimidin-4-ylamino]- benzenesulfonamide 12.3

N-tert-Butyl-3-[2-(4-imidazol-1- ylmethyl-phenylamino)-5-methyl-pyrimidin-4-ylamino]- benzenesulfonamide 8.42

N-tert-Butyl-3-{2-[4-(2-hydroxy- ethoxy)-phenylamino]-5-methyl-pyrimidin-4-ylamino}- benzenesulfonamide 20.3

N-tert-Butyl-3-{5-methyl-2-[4- (4-oxy-morpholin-4-ylmethyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 48.6

N4-(4-Chloro-3-methoxy- phenyl)-5-methyl-N2-(4-piperazin-1-ylmethyl-phenyl)- pyrimidine-2,4-diamine 15.2

N-tert-Butyl-3-{5-methyl-2-[4- (2-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 34.3

N-tert-Butyl-3-{5-methyl-2-[4- (2-methyl-imidazol-1-ylmethyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 21.9

N-tert-Butyl-3-[5-methyl-2-(4- pyridin-4-ylmethyl-phenylamino)-pyrimidin-4- ylamino]-benzenesulfonamide 80.7

N-tert-Butyl-3-[5-methyl-2-(4- morpholin-4-yl-phenylamino)-pyrimidin-4-ylamino]- benzenesulfonamide 12.1

N2-(4-(1H-pyrazol-1-yl)phenyl)- N4-(3-tert-butylphenyl)-5-methylpyrimidine-2,4-diamine 151

N4-(7-chloro-1H-indol-4-yl)-5- methyl-N2-(4-((piperazin-1-yl)methyl)phenyl)pyrimidine-2,4- diamine Hydrochloride 694

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)pyrimidine- 2,4-diamine Hydrochloride 38.4

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(2-methyl-1H-imidazol-1-yl)phenyl)pyrimidine- 2,4-diamine Hydrochloride 94.1

N-tert-Butyl-3-[5-methyl-2-(4- [1,2,4]triazol-1-ylmethyl-phenylamino)-pyrimidin-4- ylamino]-benzenesulfonamide 35.4

N-tert-Butyl-3-{5-methyl-2-[4- (4-methyl-imidazol-1-yl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 41.7

2,N-Dimethyl-5-{5-methyl-2-[4- (2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 127

N-tert-Butyl-2-methyl-5-{5- methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin- 4-ylamino}-benzenesulfonamide 44.4

N-tert-Butyl-3-[5-methyl-2-(4- [1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-ylamino]- benzenesulfonamide 41.4

N-tert-Butyl-3-{5-methyl-2-[3- (1H-tetrazol-5-yl)-phenylamino]-pyrimidin-4-ylamino}- benzenesulfonamide 55.9

N-tert-Butyl-5-[2-(4-imidazol-1- yl-phenylamino)-5-methyl-pyrimidin-4-ylamino]-2-methyl- benzenesulfonamide 88.2

N-tert-Butyl-3-{5-methyl-2-[4- (pyrrolidine-1-carbonyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 33.5

N-tert-Butyl-3-{5-methyl-2-{4- (morpholine-4-carbonyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 32.9

N-tert-Butyl-3-{5-methyl-2-[4- (piperazine-1-carbonyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 69

N-tert-Butyl-3-{5-methyl-2-[4- (1H-tetrazol-5-yl)-phenylamino]-pyrimidin-4-ylamino}- benzenesulfonamide 96.7

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(1- morpholinoethyl)-phenyl)pyrimidine-2,4-diamine Hydrochloride 19.9

3-{2-[4-(4-Acetyl-piperazin-1- yl)-phenylamino]-5-methyl-pyrimidin-4-ylamino}-N-tert- butyl-benzenesulfonamide 18.6

N4-(3-tert-butylphenyl)-5- methyl-N2-(4-(piperidin-4-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 20.9

N-tert-Butyl-3-{5-methyl-2-[4- (1-morpholin-4-yl-ethyl)-phenylamino]-pyrimidin-4- ylamino}-benzenesulfonamide 29.7

5-methyl-N4-(2,3- dimethylphenyl)-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 16

N4-(4-chloro-2-methylphenyl)-5- methyl-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 15.9

5-methyl-N4-(3,4- dimethylphenyl)-N2-(4-(4- methylpiperazin-1-yl)phenyl)pyrimidine-2,4- diamine Hydrochloride 16.6

Example 245 Determination Of Efficacy Of Selected Compounds

HEL, CTLL-2 & normal human dermal fibroblasts (NHDF) were from theAmerican Tissue Culture Collection Rockville, Md.). BaF/3 cells wereobtained from DKFZ Cancer Research Center (Heidelberg, Germany).

BaF/3, HEL & NHDF cells were grown in RPMI 1640 medium (Gibco BRL,Gaithersburg, Md.) supplemented with penicillin, streptomycin,L-glutamine, and 10% fetal bovine serum (FBS). CTLL-2 cells were grownin the same media further supplemented with 20 U/mL recombinant IL-2(Hoffmann-LaRoche, Nutley, N.J.). Plasmid containing the human JAK2coding sequence was purchased from Invitrogen (Madison, Wis.).JAK2^(V617F) cDNA was generated by using site-directed mutagenesis tointroduce the V617F mutation into the human JAK2 coding sequencefollowed by verification using two-directional sequencing. This cDNA wassubsequently subcloned into a retroviral vector and transduced intoBaF/3 cells. Permanently transduced BaF/3 cells expressing JAK2^(V617F)were selected and maintained with 1 mg/ml G418. GFP was introduced intothis cells by lentiviral transduction using pLenti6-GFP (Invitrogen)followed by selection with blasticidin and confirmation of GFPexpression using FACs analysis.

Cell proliferation assay was performed using the XTT cell proliferationkit according to the manufacturer's instructions (Roche, Alameda,Calif.). In brief, approximately 2.5×103 cells were plated in triplicateinto microtiter-plate wells in 100 μL RPMI growth media plus variousdoses of XLV. After 72 hour incubation twenty microliters of XTT wasadded to the wells and allowed to incubate for 4-6 hours. The coloredformazan product that is formed was measured spectrophotometricallyusing the Vmax spectrophotometer (Molecular Devices, Sunnyvale, Calif.)at 450 nm with correction at 650 nm. IC50 values were determined usingthe GraphPad Prism 4.0 software (San Diego, Calif.), wherefore OD valueswere plotted on y-axis (linear scale) and concentration (mM) on thex-axis (log scale). Data was subjected to a non-linear regression fitanalysis and IC₅₀ values were determined as the concentration whichinhibited proliferation 50%.

Proliferation EC50:

-   HEL—270 nM-   Baf3:JAK2V617F—297 nM-   Control data: IL-2-induced JAK3-dependent proliferation—3395 nM-   Control data: Normal human dermal fibroblast control—6487 nM    Apoptosis Assays

BaF/3-JAK^(V617F) cells cultured in growth medium (RPMI, 10% FBS, 1mg/ml G418 and 10 μg/ml blasticidin) were treated with XLV at 1, 3 and10 μM for 24 h. Following harvesting cells by centrifugation at 890 RCF(relative centrifugation force) for 5 min, genomic DNA was isolated fromcell pellets using a DNA isolation kit (Puregen, Chino, Calif.). 5 μggenomic DNA of each sample was subjected to 1.2% agarose gelelectrophoresis to detect genomic DNA fragmentation (DNA ladderingassay). As a control, adherent normal human dermal fibroblasts (NHDF)cultured in growth medium (Cambrex, Walkersville, Md.) at 60% confluencewere treated with XLV as described above. Following 2 washes with icecold PBS, genomic DNA was isolated from the NHDF cells for agarose gelelectrophoresis.

Immunoblotting

BaF/3-JAK^(V617F) cells treated with XLV or vehicle control werecentrifuged, washed 2× with ice-cold PBS and lysed using RIPA buffer.Protein concentration was determined using the BCA method (Pierce,Rockford, Ill.) and 100 μg of total cellular protein of each sample in1× Laemmli buffer were subjected to Western blot analysis. The proteinblot was probed with an anti-phospho-STAT5 (Tyr694/699) (UpstateBiotechnology, Charlottesville, Va.), subsequently stripped andre-probed with an anti-STAT5 antibody (Cell Signaling Technology,Danvers, Mass.). The phospho-STAT5 or STAT5 protein was visualized bythe enhanced chemoluminescence method (Pierce). In vivo signalingstudies were done in a similar fashion. Briefly, on day 11 after cellinjection, animals were orally dosed with either vehicle or 100 mg/kg ofXLV. Spleens were harvested 7 h after dosing and quickly homogenized ina FastPrep machine (Qbiogen, Irvine, Calif.). 100 μg of each spleenhomogenate were subjected to Western blot analysis. The protein blot wasprobed with an blot was probed with an anti-phospho-STAT5 (Tyr694/699)(Upstate Biotechnology, Charlottesville, Va.), subsequently stripped andre-probed with an anti-STAT5 antibody (Cell Signaling Technology,Danvers, Mass.). The phospho-STAT5 or STAT5 protein was visualized bythe enhanced chemoluminescence method (Pierce). In vivo signalingstudies were done in a similar fashion. Briefly, on day 11 after cellinjection, animals were orally dosed with either vehicle or 100 mg/kg ofXLV. Spleens were harvested 7 h after dosing and quickly homogenized ina FastPrep machine (Qbiogen, Irvine, Calif.). 100 μg of each spleenhomogenate were subjected to Western blot analysis. The protein blot wasprobed with an anti-phospho-STAT5 (Tyr694/699) and subsequently with ananti-STAT5 antibody and visualized by the enhanced chemoluminescencemethod.

FACs Analysis of Circulating Tumor Burden

On day 11 after injection of BaF/3-JAK2^(V617F) cell suspension, 1 mLblood was collected by a terminal cardiac bleeding method from one mousethat received vehicle, moreover, 0.1 mL blood was collected by anon-lethal retro-orbital collection method from 10 mice of each of thethree groups dosed with 10, 30 or 100 mg/kg of XLV and pooled togetherwithin the dose groups. Blood mono-nucleated cells were isolated by aFicoll (Sigma-Aldrich, St. Louis, Mo.) cushion centrifugation method(600 RCF and 30 min). The isolated cells were subjected to FACS analysisto determine the percentage of GFP positive BaF/3:JAK2^(V617F) cells.The results are shown on the following chart.

Circulating Tumor Model

SCID mice were intravenously injected with BaF/3 cells expressingJAK2^(V617F) and GFP. XLV was dosed orally at the indicated dosesbeginning 3 days after infusion and ending 20 days after infusion. Onday 11 blood was taken from animals in each group and subjected to FACsanalysis to determine the percentage of circulating cells which were GFPpositive. In a parallel study animals were treated as described abovewith the exception that they were given a single 100 mg/kg dose of drugon day 11 followed 4 hours later by sacrifice and analysis of STAT5phosphorylation in the tumor-bearing enlarged spleen. The results areshown on the following chart.

Ocular Exposure and Efficacy Data

Exposure data of compounds at 0.1% via eye drop administration:

On topical dosing of compounds formulated as 0.1% doses in 0.2%tyloxapol/1% HPMC/4% Mannitol, exposure levels in found in back of theeye tissues of the mouse are shown at two different time points, namelyat 2 h and at 7 h. The efficacy data for selected compounds are shown inTable 2. TABLE 2 Concentration (nM) in mouse ocular tissues followingbilateral topical instillation of 0.1% formulation QDX1 Formulationconcentration for Concentration (nM) selected compounds Time (hr) retinaSclera/choroid Cornea 0.1% XVII 2 495 6040 8840 6 351 2970 3780 0.1%XXXVI 2 816 7250 7870 7 11200 34800 18600 0.1% XLIV 2 406 4840 103000 7321 3180 26600 0.1% LXXXII 2 267 2340 69900 7 592 2250 45400 0.1% LXXIV2 2120 6090 45000 7 2150 7350 21000

Example 246 Compound XVII in an Ocular Efficacy Study in anOxygen-induced Retinopathy (OIR) Model

Compound XVII was tested using the mouse oxygen-induced retinopathy(OIR) model, in which retinal neovascularization is triggered by cyclingmouse pups from normoxia to hyperoxia and then back to normoxia. Littersof C57BL/6 mice were transferred to a hyperoxic environment (70% O₂)starting on postnatal day 7 (P7). After 5 days, litters were returned toa normoxic environment (21)% O₂), where they were then maintained for anadditional 5 days, during which time they received topical applicationsof either compound XVII or an appropriate vehicle. At the end of thisperiod, retinal whole-mounts were prepared and stained with afluorescently-labeled lectin (BSL I) that recognizes murine endothelium.Finally, digital images were obtained by fluorescence microscopy andanalyzed with an image analysis software program in order to quantifyvascular area. In one study, animals dosed with a 0.1% formulation ofcompound XVII twice daily (bid) showed a 29% reduction in vascular areaas compared to vehicle-treated animals (P<0.05, n=11-15); in a secondstudy, a 22% reduction was observed (P<0.02, n=6). The results aresummarized in Table 3. TABLE 3 Vascular Area % Change vs. Study #Treatment Group (mm², mean ± SD) Vehicle Control OIR-004 Vehicle 4.9 ±1.6 — 0.1% XVII 3.5 ± 0.6 −29% OIR-007 Vehicle 8.3 ± 0.8 — 0.1% XVII 6.4± 1.6 −22%

Example 247 Using Compound LVII for the Treatment of MyeloproliferativeDisorders

Compound LVII was tested as a potential kinase inhibitor to be used forthe treatment of myeloproliferative disorders. The results areillustrated on FIGS. 1-9. As shown by FIG. 1, JAK2 transmitsproliferation and survival signals from cytokine receptors. FIG. 2demonstrates a co-crystal of compound LVII with JAK2 kinase, thusshowing that crystallography and molecular modeling enabledidentification of key interaction sites and discovery of potent,selective ATP competitive JAK2 inhibitors. FIG. 3 shows thatJAK2^(V617F) mutation is present in a large number of patients with anunmet clinical need. For example, the prevalence of was found in 99% ofPolycythemia Vera, 71% of essential thrombocythemia, and 56% ofmyelofibrosis with myeloid metaplasia. Typically, this type ofdisease-dependence on a single kinase is rare. Complications typicallyinclude splenomegaly, bleeding, thrombosis, risk of leukemicprogression, and treatment is unsatisfactory using hydroxyurea,interferon-α, phlebotomy, or anagrelide.

Compound LVII was profiled in 223 kinases. IC₅₀ was <50 for thefollowing kinases: JAK2—3 nM; JAK2^(V617F)—3 nM; Flt3—15 nM; and Ret—48nM. The same for primary anti-target (JAK3) was 1030 nM. Table 4summarizes the potency and selectiveness data of compound LVII as aninhibitor of JAK2 kinase. TABLE 4 Primary JAK Family Selectivity TargetProfile (X-fbld selectivity) JAK2 IC₅₀ JAK2 vs. JAK2 vs. JAK2 vs.Compound (nM) JAK3 JAK1 TYK2 LVII 3 343 35 135

FIG. 4 shows that compound LVII inhibits JAK2 in cells leading toinhibition of proliferation and induction of apoptosis in HEL cellsexpressing JAK2^(V617F). FIG. 5 shows that compound LVII selectivelyreduces erythrocyte colony formation in human stem cells. To obtain thedata shown on FIG. 5, human stem cells were transduced with a retroviruscontaining either the empty vector, JAK2^(V617F) or JAK2 wild type andthen evaluated in colony forming assays in the presence of 300 nMcompound LVII. Erythrocyte colony formation was only inhibited in cellsexpressing JAK2^(V617F), suggesting that compound LVII is more active incells with a mutationally active pathway than control normal cells.

FIG. 6 shows that compound LVII selectively reverses engraftment ofhuman stem cells expressing JAK2^(V617F)—human stem cells prepared asdescribed in above were injected into the liver of 1 day oldimmunocompromised mice and cell engraftment was allowed to progress for4 weeks. Consistent with the results shown on FIG. 5, stem cells bearingJAK2^(V617F) experienced a reversal of engraftment when that compoundLVII was dosed orally, while mice bearing normal stem cells or stemcells bearing JAK2 wild type had no change in engraftment.

FIG. 7 shows that orally administered compound LVII inhibitsJAK2^(V617F) signaling in vivo leading to increased survival in aBaf3/JAK2^(V617F) system. Baf3 cells expressing JAK2^(V617F) wereinjected into SCID mice leading to a splenomegaly and death. Orallyadministered compound LVII inhibited JAK2 signaling in the enlargedspleens of day 11 animals leading to a significant dose-dependentsurvival advantage.

FIG. 8 shows that orally administered compound LVII reversespolycythemia vera-like symptoms in mice. The disease was induced byreplacing the bone marrow of irradiated C57 mice with donor marrow thathad been transduced with lentiviral JAK2^(V617F). This results in anaggressive polycythemia vera-like phenotype characterized by elevatedhematocrit, leukocytosis and splenomegaly. The disease was allowed toprogress for 32 days prior to drug administration at which point themice had dramatic disease-like symptoms as evidenced by a hematocrit of90% at treatment start. Oral administration of compound LVII for 42days, ⅓ of the RBC half-life, resulted in a dose-dependent resolution ofthese PV-like, JAK2^(V617F)-induced clinical symptoms.

In sum, compound LVII is active in vitro against cultured andpatient-derived cells bearing the JAK2^(V617F) mutations. In contrast,activity is much less against hematopoietic cells in which the JAK-STATpathway is not activated by mutations. In vivo, oral administration ofcompound LVII reverses mutant cell engraftment and polycythemia-likesymptoms in multiple animal models of the disease. This includes studiesperformed using a bone marrow transplant model in which normal mousemarrow is replaced with marrow expressing JAK2^(V617F). After allowing a1 month engraftment period in this model oral administration of compoundLVII reversed the polycythemia, leukocytosis, extramedullaryhematopoiesis and splenomegaly in a statistically significant,dose-dependent manner.

Example 248 Design of Inhibitors Targeting JAK2

As discussed above, somatic mutations in JAK2 (JAK2^(V617F)) and in theassociated receptor kinases (MPLW515L/K) play a role in keeping the JAK2pathway constitutively active, and are associated with the pathogenesisof the myeloproliferative disorders (MPDs), such as polycythemic vera(PV), essential thrombocythemia (ET) and myelofibrosis with myeloidmetaplasia (MMM). JAK2 pathway dysregulation gives proliferative andsurvival advantages to hematopoietic precursors. Therefore, JAK2inhibitors may find therapeutic utility in myeloid disease states inwhich the JAK2 pathway is involved

JAK3 does form one co-crystal structure with an inhibitor (1YVJ, FIG. 9)in the PDB. This structure is, however, exceptional, and there were noother known JAK crystal structures. Based on this JAK3 crystalstructure, we built a JAK2 homology model has been built to guidecompound design by medicinal chemistry.

The JAK2 binding model has been validated via X-ray crystallography anda limited screen of a select set of compounds give the initial hits withJAK2 IC50 of 2-10 μM (Table 5). TABLE 5 Initial Screening Hits for JAK2Compound Structure JAK2 (IC₅₀, nM) 1

6240 2

10500 3

2040

However, molecular modeling shows that there are significantintra-molecular conflicts due to 2′-Cl and the 5-CN group in compound 2of Table 5 (see, FIGS. 10 & 11). Therefore, to reduce intra-molecularconflicts, compounds 4-6 were synthesized and showed significantenhancement of potency toward JAK2 (Table 6) TABLE 6 Compound StructureJAK2 (IC₅₀, nM) 4

105 5

53 6

8

Furthermore, the principles for design, synthesis, and SAR have beendeveloped starting from the 2-10 μM hits to obtain low nM inhibitors ofJAK2. The results can be summarized as follows. SAR for the P3 region isshown in Table 7. As can be seen from the results presented in table 7,the 5-position Me in the P3 region enhances JAK2 inhibition while the CNgroup on same position decreases JAK2 inhibition (2 vs 3 & 4 vs 5). Atthe same time, the 6-position Me group is not well tolerated (7 vs 8).However, the O-linker on the 4-position of the P3 region is toleratedbut there is preference for the NH linker (9 vs 10). Finally, theNMe-linker on the 4-position of the P3 region significantly decreasesJAK2 inhibition (6 vs 11).

SAR of the P4 region is shown in Table 8. As can be seen from Table 8,2,5-di-substituted phenyl ring is not well tolerated in the P4 region (4vs 12, but ) the 3-position on the phenyl ring is well tolerated.Examples include electron donating groups, Cl (14), OMe (15), electronaccepting groups, OCF₃ (17), NO₂ (18), sterically hindered groups bothhydrophobic and hydrophilic, tBu (9), SO₂NH₂ (19), SO₂NHR (20-21),SO₂NRR′ (22-25), SO₂R (26) and piperidine (27-28). 3-OH substitutedphenyl is less tolerated compared to 3-OMe (16 vs 15). Also, caboxamideis less tolerated in the 3-position of the P4 region (29-30). TABLE 7Compound Structure JAK2 (IC₅₀, nM) 2

10500 3

2040 4

105 5

53 7

46 8

>10000 9

7 10

58 6

8 11

4900

TABLE 8 Compounds 4 & 12

JAK2 JAK2 Compound P4 (IC50, nM) Compound P4 (IC₅₀, nM) 4

tC5 12

1330 Compounds 13-18

JAK2 JAK2 Compound P4 (IC50, nM) Compound P4 (IC₅₀, nM) 13

17 17

21 14

21 18

61 15

53 9

7 16

203 Compounds 19-35

JAK2 JAK2 Compound P4 (IC50, nM) Compound P4 (IC₅₀, nM) 19

14 28

8 20

5 29

541 21

12 30

830 22

17 31

304 23

19 32

14 24

25 33

9 25

21 34

5 28

8 36

4 27

42 Compounds 36-39

JAK2 JAK2 Compound P4 (IC50, nM) Compound P4 (IC₅₀, nM) 36

20 38

12 37

28 39

1050

The P4 region tolerates several 2,3-fused bicyclic moieties, such asbenzodioxole (32), indole (33-35), naphthalene (36), benzothiophene(37-38). However, the P4 region does not tolerate the pyridine ring (31vs 13) or the isoquinoline ring (39). SAR of the P2/P1 Region is shownin (Table 9) TABLE 9

JAK2 JAK2 (IC50, (IC₅₀, Compound P2/P1 nM) Compound P2/P1 nM) 40

12 49

19 20

6 50

18 41

8 51

22 42

7 52

22 43

18 53

36 44

29 54

49 45

12 55

190 46

13 56

10 47

7 57

316 48

7 58

707

As can be seen from table 9, the P2 region tolerates benzene rings(40-55) and pyridine rings (56). No other hetero-aromatic rings aretolerated—data not shown. The P1 region tolerates a variety ofsolubilizing groups. Examples include 4-ethyoxypyrrolidine (40, 54-55),4, and 3-piperazine (22, 41-44), 4, and 3-mopholine (45-47), pyrazole(49-50), and imidazole (51). However, the P1 region does not toleratethe 3-sulfonamide group (57-58).

Example 249 Structure-Activity Relationship Studies for Optimization ofJAK2 Potency

As discussed above, somatic mutations in JAK2 (JAK2^(V617F)) and in theassociated receptor kinases (MPLW515L/K), play a role in keeping theJAK2 pathway constitutively active and are associated with thepathogenesis of the myeloproliferative disorders (MPDs). JAK2(^(V617F))is widely distributed in the MPDs including in a majority (>95%) ofpolycythemia vera (PV) cases, and approximately half of the patientswith essential thrombocythemia (ET) or agnogenic myeloid metaplasia(AMM). Using structure based drug design, a series of novel and potentcompounds targeting JAK2T were designed and synthesized. Subsets of thisseries were subsequently optimized for selectivity against the highlyhomologous JAK3 kinase.

As seen from the sequences shown on FIG. 12, there is high homologybetween JAK2 and JAK3 at the ATP binding site. Using subtle differencesin the sequences JAK3 was de-selected because it is an immunosuppressivetarget. As discussed above, except for one co-crystal structure of JAK3with an inhibitor (IYVJ), there were no known JAK family crystalstructures when we started our discovery work on JAK2. Based on the JAK3crystal structure (1YVJ), a JAK2 homology model was built to guidecompound design.

Compounds were optimized for JAK2 potency. Further SAR studies providedmultiple compounds with high JAK2 potency and de-selection of JAK3.These series of compounds occupies the ATP binding pocket of JAK2 asconfirmed by X-ray crystallography, and the enzyme pocket walls arepushed significantly closer to the ligand in JAK2 compared to JAK3resulting in the absence of a back pocket in JAK2.

As indicated by Table 10, substitutions at the 2-, 3-, or 4-positionscan enhance JAK2 vs. JAK3 selectivity, but there is no clear trend toexplain the JAK2 vs. JAK3 selectivity (for example, 3 vs. 4). P4 regioninitial selectivity SAR is shown in Table 10. Several other moieties inthe P1 region has been also known as potent inhibitors of JAK2. Tofurther explore the JAK2 vs. JAK3 selectivity these other P1 sub-serieswere examined, one of which is shown in Table 11. TABLE 10

Com- JAK2 JAK3 JAK3/ pound P4 moeity IC₅₀ (nM) IC₅₀ (nM) JAK2 1

8 69  9x 2

7 71 11x 3

9 197 21x 4

12 350 28x 5

1 45 39x

TABLE 11

JAK2 JAK3 Compound P4 moiety IC₅₀ (nM) IC₅₀ (nM) JAK3/JAK2 6

6 19  4x 7

7 71 11x 8

8 169 28x 9

19 678 36x 10

10 431 47x

The complex relationship between moieties in the P4 region and the P1region is clearly shown with 5 (Table 10) vs. 6 (Table 11).Substitutions at the 2- or 3-positions in the P4 region again enhanceJAK2 vs. JAK3 selectivity.

Further optimization was achieved by holding the P4 region constant andprobing changes in the P1 region. A representative sub-series is shownin Table 12.

The synergistic effect of the t-butyl sulfonamide moiety in the P4region with the group in the P1 region is exemplified by 8 (Table 11)vs. 16 (Table 12).

The inhibitors make a hinge interaction and occupy the pocket takingadvantage of key hydrophobic interactions in the P4 area, along with asolubilizing group in the solvent exposed P1 region. TABLE 12

JAK2 JAK3 JAK3/ Compound P1 moiety IC₅₀ (nM) IC₅₀ (nM) JAK2 11

13 709  57x 12

7 533  73x 13

30 2980 100x 14

34 3600 105x 15

12 1490 121x 16

8 1330 158x

Example 250 Inhibitors of JAK Kinase for the Treatment ofMyeloproliferative Disorders

A series of structurally novel compounds capable of inhibitingJAK2^(V617F) were designed and synthesized. Compounds were identifiedwhich potently inhibited JAK2 enzyme, with potencies as low as 1 nM.Subsets of this group were subsequently identified which were highlyselectivity against undesirable off-target kinases, including up to 100×selectivity versus JAK3 and potently inhibiting less than 5% of thekinases evaluated in a commercially available, phylogenetically diversepanel of 75 kinases.

Compounds were then advanced into in vitro assays in JAK2^(V617F)transformed cell lines in which exemplary compounds potently inhibitedJAK2-driven cell proliferation and STAT5 phosphorylation. Compounds fromthis series were subsequently shown to be orally available in multiplespecies and efficacious in rodent models of JAK2-driven disease. Theresults are demonstrated on FIGS. 13-21.

FIG. 13 shows that small molecule JAK2 inhibitor development is enabledby location of V617F mutation distal from ATP binding pocket. FIGS. 14and 16 demonstrate the use of molecular modeling to enable rationaldesign of a large number of potent small molecule inhibitors of JAK2.FIG. 15 demonstrates the differences between JAK2 and JAK3 selection. Ascan be ween from FIG. 15, there are few amino acid differences aroundthe ATP binding site that can be exploited for selectivity.

FIG. 17 demonstrates that compound LVII is highly selective across abreadth of kinases. Compound LVII, an exemplary JAK2 inhibitor, wasevaluated internally (upper box) and externally against multiplekinases. Compound LVII is 83 times more potent on JAK2 than JAK3, and500 nM compound LVII inhibited only 2 kinases in a broad,phylogenetically diverse panel from InVitrogen—Flt3 and Ret.

FIG. 18 demonstrates that compound LVII selectively inhibitsJAK2-mediated cell proliferation. Compound LVII potently inhibitsJAK2^(V617F)-driven proliferation in HEL cells, but is about 10 timesless potent at inhibition of IL-2 driven proliferation of CTLL-2 cells.In a further study, HEL cells were treated with the indicatedconcentration of compound LVII for 12 hours followed by lysis andanalysis of STAT5 phosphorylation and apoptosis (DNA laddering). Thenresults provided on FIG. 19 demonstrate that compound LVII reducesJAK2-induced STAT5 phosphorylation and induces apoptosis in adose-dependent manner.

In a further experiment, compound LVII was dosed orally and PKparameters evaluated in mouse, rat and monkey. Based on this data humanPK parameters were estimated using allometric scaling, shown on FIG. 20.

In a further experiment, GFP labeled, Ba/F3: JAK2^(V617F) were injectedintravenously and allowed to establish for 3 days prior to dosing. Acompound of the invention, as shown by FIG. 21, was administered bid, atthe doses indicated on FIG. 21, which demonstrates that certaininhibitors of the present invention increase survival and reduceJAK2^(V617F) cell burden after oral dosing in rodent model. On day12-13, when vehicle animals were displaying advanced clinical signs,eyebleeds were performed for FACs analysis of GFP-expressing cells. Aparallel group of animals were dosed a single time with drug on day 11followed by extraction of their spleens and analysis of STAT5phosphorylation.

Example 251 Low nM JAK2 Selective Inhibitors Exhibiting Potent In VitroActivities with Favorable Preclinical Properties

The SAR and optimized compounds to obtain low nM JAK2 inhibitors havebeen developed. Tables 13-17 describe the SAR for the sulfonamideseries. More specifically, Table 13 demonstrates data formono-substituted sulfonamide inhibitors. Table 14 demonstrates data fordi-substituted sulfonamide inhibitors. Tables 15 and 16 demonstratesdata for SAR of P2 in para- and meta-positions, respectively. Table 17demonstrates data for P2-P1 SAR. TABLE 13

JAK2 JAK3 JAK3/ HEL Compound R IC₅₀ (nM) IC₅₀ (nM) JAK2 EC₅₀ (nM) 1 H 14402 29X 4,336 2 Me 16 266 17X 703 3

12 301 25X 490 4

6 169 28X 178 5

20 194 10X 688 6

39 196  5X 1,410HEL: Human erythroid leukemia cells expressing JAK2(V617F)

TABLE 14

JAK2 JAK3 JAK3/ HEL Compound R IC₅₀ (nM) IC₅₀ (nM) JAK2 EC₅₀ (nM) 7

10 451 45X 420 8

25 337 13X 309 9

34 363 11X 453 10

21 299 14X 409 11

17 189 11X 125

TABLE 15

JAK2 JAK3 JAK3/ HEL Compound P1 moiety IC₅₀ (nM) IC₅₀ (nM) JAK2 EC₅₀(nM) 4

6 169 28X   178 12

8 225 28X   2771* 13

12 841 70X   465 14

7 230 33X   2040* 15

13 709 55X   297* 16

5 286 57X 3,445 17

7 533 76X 4,547 18

19 1,440 76X 2,956 19

12 1,490 124X 1,032 20

34 3,600 106X 2,076 21

41 2,760 67X 1,154*Ba/F3 cells expressing JAK2(V617F)

TABLE 16

JAK2 JAK3 JAK3/ HEL Compound P1 moiety IC50 (nM) IC50 (nM) JAK2 EC50(nM) 22

18 1,070 59X 3,031 23

41 1,540 38X 1,996 24

7 606 87X 812

TABLE 17

JAK2 JAK3 JAK3/ HEL Compound P2-P1 moiety IC50 (nM) IC50 (nM) JAK2 EC50(nM) 25

23 461 20X 568 26

36 1,410 39X 1778 27

10 629 63X 4700

The top left from the P4 region (FIG. 10) is used to illustrate theoptimization of the inhibitors in this series. The choice of N-methylphenyl piperazine as our starting P2-P1 moiety was based on previous SARstudies. As shown in Tables 13 and 14, the phenyl group in the P4 regiondisplays high tolerance to a variety of mono- and di-substitutedsulfonamide groups (in vitro JAK2 IC₅₀ in the range of 6-40 nM).

Sulfonamide as part of the P4 aryl moiety provides compounds with lesspotency against JAK3 (up to ˜50-fold vs. JAK2, see compound 7 in Table14).

Substitution on the sulfonamide group increases compound cell activity(1 vs. 2-6 or 1 vs. 7-11). In the mono-substituted sulfonamidecompounds, substitution with branched alkyl groups provides betterselectivity towards JAK2 compared to that seen with the cyclo alkyls (3or 4 vs. 5 and 6). In a similar fashion to that seen in themono-substituted sulfonamide compounds, cycloalkyl di-substitution leadsto less selective inhibitors (7 vs. 8-11).

Based on the JAK3 de-selection and favorable cellular potency, the focuswas on the tert-butyl sulfonamide series. Further SAR studies on thetert-butyl sulfonamide series are presented in Tables 15-17. As shown inthe biochemical data (Tables 15 and 16), the phenyl group in the P2region displays high tolerance to a variety of P1 moieties, whichenhance solubility and optimize de-selection from JAK3.

All compounds maintain potent activity for JAK2 (5-40 nM) andde-selection from JAK3 (ca. 30-120X). Hetero-cycles in the P1 regionwith basic nitrogen and hetero-aryl groups are well tolerated, withhetero-aryls provide better selectivity (see compounds 19 and 20 inTable 15). Both meta- and para-substitutions maintain good potency andselectivity (12 vs. 22 or 14 vs. 23 or 15 vs. 24). In the cellularassay, compounds with P1 hetero-aryls are less tolerated than that ofhetero-cycles. Meta-substitution, in general, provide compounds with μMcellular potency. Compounds with para-substitution easily achieve ca.200-500 nM cellular potency.

As shown in Table 17, compounds with the pyridyl group and substitutedaryls in the P2 region are well tolerated and maintain high selectivityfor JAK2 in the biochemical assay (see compounds 25-27). Both compounds25 and 26 with substituted aryl in the P2 region exhibited decentcellular activity (ca. 500-2000 nM).

The in vitro cellular data are presented next. Ba/F3 cells were treatedwith the indicated concentration of A for 24 h followed by lysis andanalysis of STAT5 phosphorylation and apoptosis (DNA laddering). GFPlabeled, Ba/F3: JAK2(V617F) cells administered i.v. to SCID mice. On day3, dose with compound A (10, 30, 100 mg/kg p.o. b.i.d.). Survival asendpoint; FACS analysis of circulation tumor burden.

Group of animals were dosed a single time with A on day 11 followed byextraction of their spleens after 5 h and analysis of STAT5phosphorylation. Compound A inhibits of JAK2(V617F)-induced proteinphosphorylation in the spleen of mice implanted with Ba/F3: JAK2(V617F)cells

As can be seen, compounds A and B (FIG. 23) potently inhibitJAK2(V617F)-mediated proliferation in human ethyroid leukemia (HEL)cells, and compound A increases survival in a dose dependent manner inthe rodent model (FIG. 24). Dose-dependent survival benefit correlateswith dose-dependent reduction in mutant-bearing circulating tumor cellsmeasured at day 12 (FIG. 25).

Example 252 Inhibition of JAK2 V617F-Induced Erythroid Skewing ofHematopoietic Stem Cell Differentiation with a Selective JAK2Anatagonist

It was investigated whether a selective JAK2 inhibitor decreased Jak2V617F induced erythroid differentiation. Normal peripheral blood andcord blood (CB) HSC (CD34+/CD38−/CD90+) were clone sorted using FACSAria and transduced with Lenti viruses expressing wild-typeJAK2(JAK-WT), mutant JAK2 (JAK-MT), Lenti-backbone (BACKBONE) orNo-vector in methocult media +/− compound LVII JAK2 inhibitor. Samplesfrom PV patients were sorted as well to media +/−30-600 nM of aselective JAK2 inhibitor, +/− compound LVII or directly to RNA lysisbuffer. Colonies were scored at day 14.

Cord Blood Progenitors (CD34+/CD38−) transduced with JAK-WT, JAK-MT orBACKBONE in combination with luciferase-GFP lentivirus or PV Progenitorsmarked with luciferase-GFP lentivirus, were transplantedintrahepatically 48 hrs after transduction to neonatal Rag2/gama-chainKO mice.

FIG. 26 shows: photomicrographs (50×) of normal cord blood HSC day 14colonies with no vector, backbone vector, JAK2 wild-type (wt) or JAK2V617F (upper) and Human cord blood HSC derived colonies were collectedafter 14 days in methylcellulose culture and murine JAK2 PCR verifiedtransduction with the lentiviral vectors (lower).

Transduction of cord blood HSC with the mutant Jak2 vector resulted inskewed erythroid colony formation compared to wild-type Jak2, vectoralone and untransduced HSC (FIG. 26: n=3). RT-PCR with murine Jak2compared to wild-type Jak2, vector alone and untransduced HSC (FIG. 26:n=3). RT=PCR with murine Jak2 specific primers resulted in 900 bpfragments corresponding to murine Jak2 from colonies transduced with thewildtype and mutant Jak2 and confirmed by sequencing, but not those fromcolonies transduced with the vector alone or the untransduced cells(FIG. 26).

Like the results in cord blood cells, adult peripheral blood CD34+ cellstransduced with the mutant Jak2 developed a skewed developmentalpattern, with far greater erythroid colony formation compared towild-type Jak2 or vector alone. In megacult assays, CD34+ cellstransduced with the mutant Jak2 had similar megakaryocytic potential aswild-type Jak2 or vector alone.

FIG. 27 shows the results of treatment of human cord blood HSC(CD34+CD38−CD90+Lin−) transduced with lentiviral backbone, JAK2 WT orJAK2 V617F(Mutant) vectors, (25 cells/well in 96 well plate withMethylcellulose), with or without 300 nM of +/− compound LVII, aselective JAK2 inhibitor, and colonies scored on day 14.

FIG. 28 shows the results of an experiment in which HSC(CD34+CD38−CD90+Lin), progenitors (CD34+CD38+Lin−) or common myeloidprogenitors (CMP; CD34+CD38+IL3Ralpha+CD45RA−Lin−) cells from two JAK2V617F+ PV patients were clone-sorted (25 cells/well) with the aid of aFACS Aria and treated with 0,30,100,300 or 600 nM of compound LVII inmethylcellulose. Differential colony counts were performed on day 14.These results mirrored those seen with the JAK2 V617F transduced cordblood HSC (FIG. 27) in that compound LVII selectively inhibited JAK2V617F-skewed erythroid differentiation

Untransduced HSC served as a control. As can be seen, these experiments(n=3) demonstrated inhibition of JAK2 V617F skewed erythroid colonyformation. Addition of compound LVII (300 nM), inhibited mutantkinase-induced erythroid colony formation (FIG. 27) in 3 experimentswhile 100-300 nM was inhibitory to PV (n=2 patients) HSC and progenitors(FIG. 28).

FIG. 29 shows the results of an experiment in which FACS cloned HSC andprogenitors from a PV patient or normal human cord blood were markedwith Luc-GFP lentivirus and 48 hrs later transplanted intrahepaticallyin new-born immunodeficient mice. Mice were analyzed for bioluminescencewith the aid of an IVIS 200 in vivo imaging system (Xenogen Inc). Micewere sacrificed 8 weeks after transplantation. Hematopoietic organs(spleen, liver, bone marrow and thymus) were harvested for FACS analysiswhich demonstrated enhanced erythroid by PV HSC and progenitors comparedwith their normal counterparts

Transplantation of PV patient HSCs (CD34+,CD38−CD90+Lin−) in neonatalimmunodeficient mice (RAG₂−/−gamma_(c)−/−) resulted in enhancederythroid engraftment compared with more committed PV progenitors andnormal HSC (FIG. 29).

FIG. 30 shows the results of an experiment in which FACS purified normalcord blood progenitors were transduced with backbone JAK2WT or JAK2V617F and marked with Luc-GFP lentivirus for 48 hrs. Subsequently, cellswere transplanted intrahepatically into newborn immunodeficient mice.Mice were analyzed for bioluminescence in an IVIS 200 and sacrificed 8weeks after transplantation. Hematopoietic organs (spleen, liver, bonemarrow and thymus) were harvested for FACS analysis. This analysisdemonstrated increased human myeloid and erythroid engraftment in thesetting of JAK2 overexpression.

Analysis of mice transplanted with cord blood progenitors(CD34+CD38−Lin−) transduced with JAK-WT, JAK-MT or BACKBONE incombination with luciferase-GFP lentivirus revealed enhanced engraftmentcapacity of JAK2 overexpressing cells (FIG. 30).

Example 253 Selective Inhibition of JAK2 Kinase by Compound XLV forTreatment of Myeloproliferative Disorder-Associated JAK2V617F andMPLW515L/K Mutations

The potential of compound XLV to inhibit mutations that constitutivelyactivate JAK-STAT signaling in MPD was studied. The molecular structureof compound XLV, which is one such JAK2 selective inhibitor that wasfurther characterized, is shown on FIG. 31A. A molecular model showingcompound XLV docked in the ATP pocket of JAK2 kinase, highlighting thekey interactions is shown on FIG. 31B. Compound XLV was most activeagainst JAK2 (IC50=6 nM), and exhibited selectivity for JAK2 relative toJAK3 (28× greater inhibition of JAK2) (FIG. 31C).

It was further shown that compound XLV inhibits JAK2V167F in vitro.Compound XLV inhibited the growth of Ba/F3-V617F cells with an IC50 of300 nM (FIG. 32A). In contrast, compound XLV had minimal effect on thegrowth of CTLL-2 cells, a clone of IL-2 dependent cytotoxic T-cells(IC50 of 3400 nM) (FIG. 32B). As expected, parental Ba/F3 cells werealso inhibited by compound XLV (IC50=470; data not shown), reflectingtheir dependence on signaling by wild type JAK2. Treatment with compoundXLV resulted in a dose-dependent inhibition of HEL cells that arehomozygous for the JAK2V617F allele (IC50=300 nM) (FIG. 32C). In controlexperiments, compound XLV inhibited BCR−ABL+K562 cells with an IC50=1μM.

It was also shown that compound XLV selectively induced apoptosis ofJAK2V617F-expressing cells. At 48 hours, HEL cells treated with compoundXLV showed a dose-dependent increase in annexin-V+/PI+ apoptotic cellswhen compared to untreated cells (60% at 600 nM; FIGS. 33A and 33B, leftpanels). In control experiments, compound XLV was less effective atinducing apoptosis of K562 cells (35% at 1200 nM; FIGS. 33A and 33B,right panels). Compound XLV also effectively induced apoptosis ofBalF3-V617F cells (data not shown).

Furthermore, compound XLV selectively induced cell cycle arrest ofJAK2V617F-expressing cells. After 24-hours with 600 nM compound XLV(IC50), the proportion of HEL cells in G0/G1 (40%) was greater ascompared to untreated cells (15%), indicating G0/G1-arrest (FIGS. 34Aand 34B). In control experiments, the G0/G1 fraction of K562 cellsincreased from 45% to 50% with 1200 nM compound XLV (IC50) (FIGS. 34Cand 34D).

Also, it was demonstrated that compound XLV inhibited phosphorylation ofJAK2V617F, STAT5, and STAT3 in JAK2V617F-expressing cells. In HEL cells,a dose dependent decrease in levels of phospho-JAK2V617F, phospho-STAT5,as well as phospho-STAT3 was observed with compound XLV treatment(IC50=300-600 nM) (FIG. 35). Compound XLV also potently inhibited STAT5phosphorylation in Ba/F3-V617F cells (IC50=300 nM) (data not shown).

In addition, it was shown that compound XLV effectively treatedJAK2V617F-induced hematopoietic malignancy in mice. Injection ofBa/F3-V617F-GFP cells into SCID mice produces a rapidly fatalJAK2V617F-induced hematopoietic malignancy, with latency of 11 days and100% penetrance (FIG. 36A). Recipient mice were treated with compoundXLV by gavage at the following doses: 0 mg/day (placebo control), or 20mg/kg/day, 60 mg/kg/day, or 200 mg/kg/day, each in 2 divided doses, fromdays +3 to +20 following tumor cell injection. Compound XLV treatment(200 mg/kg/day) was effective at increasing survival of affected animalsas compared to placebo (10 days; P<0.02) (FIG. 36A). Furthermore,compound XLV induced a significant dose-dependent reduction incirculating tumor cells (75% and 15% GFP+ cells in placebo− vs. 200mg/day compound XLV-treated animals, respectively; P<0.02) (FIG. 36B).Clinical benefit of compound XLV correlated with a marked decrease inSTAT-5 phosphorylation in splenic tumors, evident as early as 7 hoursafter administration of a single dose of compound XLV (100 mg/kg) (FIG.36C).

Finally, it was demonstrated, by comparison of effects on progenitorsfrom normal controls versus myeloproliferative disorder patients, thatcompound XLV inhibited hematopoietic colony formation in vitro. CompoundXLV effect on hematopoietic colony growth was studied in MPD patientscarrying either JAK2V617F (n=5) or MPLW515L/K (n=3) mutations (Table 18below).

CD34+ cells in methylcellulose (±cytokines) were plated and followedchanges in (i) colony number, (ii) colony size/morphology, and (iii)mutant colony burden, after incubation with compound XLV (0 nM, 300 nM,or 600 nM). Compound XLV more potently inhibited colonies derived fromCD34+ cells of PV or AMM patients, relative to control CD34+ cells(AMM>PV>normal) (Table 18).

Genotyping of individual colonies for JAK2V617F revealed a selectivesuppression of mutation-positive colonies in the presence of compoundXLV, for 3 of 5 PV patients (Table 18) (FIG. 37A). Similarly, singlecolony genotyping confirmed a selective suppression of MPLW515-positivecolonies with compound XLV, for 2 of the 3 AMM patients (AMM1 and AMM2)(Table 18) (FIG. 37B). TABLE 18 TG101209 effect on in vitrohematopoietic colony growth from MPD patients carrying JAK2V617F orMPLW515 mutations Cytokine-supported colonies - mutation pattern asassessed by genotyping of 575 Individual colonies Lineage-specificLineage-specific Mutation Mutation mutation burden mutation burdenpattern without pattern with without inhibitor with inhibitor Total no.inhibitor inhibitor (% mutation- (% mutation- IC₅₀ (nM) colonies (%colonies (% colonies positive colonies) positive colonies) PatientMutation Erythroid Myeloid genotyped genotyped) genotyped) ErythroidMyeloid Erythroid Myeloid Normal WT 1000  600 n/a n/a n/a n/a PV1JAK2V617F ˜600 300-600 62 HET/WT HET/WT 82 90 36 70 (85/15) (57/43) PV2JAK2V617F ˜600 ˜300 111 HET/WT HET/WT 70 55 60 20 (65/35) (60/40) PV3JAK2V617F NA 59 HOM/WT HOM/HET/WT 20 30 30 0 (23/77) (8/8/84) PV4JAK2V617F >600 ˜600 61 HOM/HET/WT HOM/HET/WT 7 10 17 10 (4/4/92)(8/11/81) PV5 JAK2V617F ˜300 300-600 47 HOM/HET/WT HOM/HET/WT 64 92 82100 (74/4/22) (92/4/4) AMM1 MPLW515K <300 ˜300 59 HET/WT HET/WT 100 90 020 (93/7) (17/83) AMM2 MPLW515K 300-600 ˜300 86 HET/WT HET/WT 100 90 2536 (90/10) (39/61) AMM3 MPLW515L 300-600 300-600 90 HOM/HET HOM/HET/WT100 100 92 90 (91/9) (71/22/7) AMM4 WT >600 300-600 n/a n/a n/a n/aPV indicates polycythemia vera;AMM, agnogenic myeloid metaplasia;WT, wild-type;HET, heterozygous;HOM, homozygous;n/a, not applicable;nM, nanomolar;NA, not available;No., number;%, percentage; andIC₅₀, inhibitor (TG101209) concentration that suppresses colony numberby 50%.

The compounds of the present invention were designed to obtainselectivity for inhibiting JAK2. While not wanting to be bound by aparticular theory, it is believed that removal of the methyl group orreplacement with hydrophilic or larger groups results in a substantialloss in activity of the compounds of the invention. In another example,it is believed that a CH is important in the pyrimidine ring or forexample, in a para position to R7 for activity and selectivity over JAK3and other JAK family kinases. Larger substitutions at R7, preferablybranched are believed to be important to maintain JAK2 activity andselectivity for the JAK2 over the other JAK family members, especiallyJAK3. An NH connected to a position between two nitrogens in thepyrimidine ring is seemingly important in the position for JAK2activity. Further, an aromatic ring connected to the above-mentioned NHis seemingly important, such as a phenyl ring. Replacement of thisphenyl ring with a pyrimidine for example results in complete loss inactivity. The portion on the right side prefers to be a heterocyclicmoiety. In the case of using aromatic heterocyclic groups there is aloss in cellular activity

Although the invention has been described with reference to the aboveexamples, it will be understood that modifications and variations areencompassed within the spirit and scope of the invention. Accordingly,the invention is limited only by the following claims.

1. A compound having the structure (A):

wherein: X is selected from a group consisting of a bond, O, C═O, SO₂,and CH₂; Y is selected from a group consisting of a bond or NR⁹; or Xand Y taken together is a bond; each of R¹ and R² is independentlyselected from a group consisting of H, C₁-C₆ substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycle, substituted or unsubstitutedaryl, and substituted or unsubstituted heteroaryl; or R¹ and R² takentogether is a bond; or R¹ and R² taken together form a moiety selectedfrom a group consisting of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m),(CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); each of p, q, r, n,m is independently an integer having the value between 0 and 6, R⁹ isselected from a group consisting of H, C₁-C₆ alkyl, C₁-C₆ cycloalkyl,C₁-C₆ branched alkyl, C₁-C₆ substituted alkyl, C₁-C₆ aminoalkyl, andC₁-C₆ hydroxyalkyl; G₀ is selected from a group consisting of N, O, H,and CH, with the proviso that if G₀ is N, then: each of R³ and R⁴ isindependently selected from a group consisting of H, C₁-C₆ alkyl, C₁-C₆substituted or unsubstituted hydroxyalkyl or aminoalkyl, C₁-C₆substituted or unsubstituted branched alkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl, or R³and R⁴ taken together form a moiety selected from a group consisting of(CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), and(CH₂)_(r)—O—(CH₂)_(m); with the additional proviso that if G₀ is N,then: R¹ and R⁹ taken together form a moiety selected from a groupconsisting of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), and(CH₂)_(r)—O—(CH₂)_(m); or R¹ and R⁴ taken together forms a moietyselected from a group consisting of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m),(CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); or R⁹ and R⁴ takentogether form a moiety selected from a group consisting of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); or R³ and R⁴ takentogether form a moiety selected from a group consisting of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁶—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); with the furtherproviso that if G₀ is O, then: R³ is selected from a group consisting ofH, C₁-C₆ alkyl and C₁-C₆ substituted or unsubstituted hydroxyalkyl oraminoalkyl, substituted or unsubstituted branched alkyl, substituted orunsubstituted cycloalkyl, substituted heterocyclic connected throughcarbon or nitrogen, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl connected through carbon or nitrogen, with nogroup R⁴; R¹ and R⁹ taken together form a moiety selected from a groupconsisting of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m),(CH₂)_(r)—SO₂—(CH₂)_(m), (CH₂)_(r)—NR⁹—(CH₂)_(m), and(CH₂)_(r)—O—(CH₂)_(m); or R¹ and R³ taken together form a moietyselected from a group consisting of (CH₂)_(m), (CH₂)_(r)—S—(CH₂)_(m),(CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); or R⁹ and R³ takentogether form a moiety selected from a group consisting of (CH₂)_(m),(CH₂)_(r)—S—(CH₂)_(m), (CH₂)_(r)—SO—(CH₂)_(m), (CH₂)_(r)—SO₂—(CH₂)_(m),(CH₂)_(r)—NR⁹—(CH₂)_(m), and (CH₂)_(r)—O—(CH₂)_(m); with the furtherproviso that if G₀=CH, then each of R³ and R⁴ is independently selectedfrom a group consisting of H, C₁-C₆ alkyl, C₁-C₆ substituted orunsubstituted hydroxyalkyl or aminoalkyl, C₁-C₆ substituted orunsubstituted branched alkyl, substituted or unsubstituted aryl, C₁-C₆substituted or unsubstituted heterocycle connected through carbon ornitrogen, and substituted or unsubstituted heteroaryl connected throughcarbon or nitrogen, or R³ and R⁴ taken together form a moiety selectedfrom a group consisting of (CHR⁹)_(r)—(CHR⁹)_(m)—(CHR⁹)_(p),(CHR⁹)_(r)—S—(CHR⁹)_(m), (CHR⁹)_(r)—SO—(CHR⁹)_(m),(CHR⁹)_(r)—SO₂—(CHR⁹)_(m), (CHR⁹)_(r)—NR⁹—(CHR⁹)_(m), and(CHR⁹)_(r)—O—(CHR⁹)_(m); G is N or CR⁶, and each G is independent ofeach other G, with the further proviso that not more than two groups Gcan be N, with the further proviso that for each CR⁶, each R⁶ isindependent of each other group R⁶. R⁵ is methyl;

wherein each of R⁶, R⁷, R⁸ is independently selected from a groupconsisting of H, C₁-C₆ substituted or unsubstituted alkyl, C₁-C₆substituted or unsubstituted alkenyl, C₁-C₆ substituted or unsubstitutedalkynyl, C₁-C₆ substituted or unsubstituted hydroxyalkyl or aminoalkyl,C₁-C₆ substituted or unsubstituted branched alkyl, C₁-C₆ substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl connectedthrough carbon or a heteroatom, substituted or unsubstituted heteroarylconnected through carbon or a heteroatom, C₁-C₆ alkoxy, a halogen, CF₃,—OCF₃, CHR³R⁴, SR³, SOR³, SO₂R³, SO₂NR³R⁴, SO₃R³, POR³, PO₂R³, PO₂NR³R⁴,PO₂CR³R⁴, PO₃R³, NR³R⁴, NO₂, CN, OH, CONR³R⁴, COR³, COOR³, NR³COR⁴,NR³CONR³R⁴, OCONR³R⁴, CSNR³R⁴, CSR³, NR³CSNR³R⁴, SCONR³R⁴, SCSNR³R⁴, andSCSNR³R⁴; or any of R⁶ and R⁷ taken together, or R⁷ and R⁸ takentogether, or R⁶ and R⁸ taken together form a moiety independentlyselected from a group consisting of —HN—CH═CH—, —HN—N═CH—, —HN—N═N—,—O(CH₂)—O—, —S(CH₂)_(n)S—, —N═CH—S—, —CH═N—O—, —CH═N—S—, —N═CH—O—,—C═N—O—, —C═N—O—, —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —O—CH═CH,and —S—CH═CH—; or R³ and R⁴ taken together form a moiety selected from agroup consisting of (CHR⁹)_(r)—(CHR⁹)_(m)—(CHR⁹)_(p),(CHR⁹)_(r)—S—(CHR⁹)_(m), (CHR⁹)_(r)—SO—(CHR⁹)_(m),(CHR⁹)_(r)—SO₂—(CHR⁹)_(m), (CHR⁹)_(r)—NR⁹—(CHR⁹)_(m), and(CHR⁹)_(r)—O(CHR⁹)_(m); A is selected from a group consisting of O, NR³,CR³R⁴, S, SO, and SO₂; G₁ is selected from a group consisting of CH, N,NH, S, and O; G₂ is selected from a group consisting of CR⁷, N, NH, S,and O, with each group R⁷ being independent of every other group R⁷; andif G₁ or G₂ is NH, S, or O, then Q is a five membered heteroaromaticring, optionally fused to a six member aromatic or non-aromatic ring;and if G₁ or G₂ is N, then Q is a five or a six membered aromatic ring,optionally fused to a six member aromatic or non-aromatic ring; with thefurther proviso that X or G₀ includes at least one heteroatom includedwith X and selected from O, S and N, or G₀ comprises at least fournon-hydrogen atoms, inclusive of the heteroatom, and R³ and R⁴, or R¹and R⁹, or R¹ and R⁴, or R⁹ and R⁴ taken together form an aromatic,heteroaromatic, cyclic or heterocyclic ring system, or if a noncyclicsystem is present, then more than one heteroatom is present, and if A isNR₃, then any of R₆, R₇ or R₈, or any combination thereof independentlyincludes at least two non-hydrogen substituents, or if A is NR₃, then Qforms a fused ring from R₆ to R₇, or from R₇ to R₈, or pharmaceuticallyacceptable salts, hydrates, solvates, crystal forms, N-oxides, andindividual diastereomers of the compound (A).
 2. A compound comprising afirst moiety chemically connected to a second moiety, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms,N-oxides, and individual diastereomers thereof, wherein the first moietyis selected from the group consisting of:

and wherein the second moiety is selected from the group consisting of:


3. The compound of claim 1, wherein the compound is selected from thegroup consisting of compounds having formulas I-CLXII:


4. The compound of claim 1, wherein the compound is


5. The compound of claim 1, wherein the compound is


6. The compound of claim 1, wherein the compound is


7. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


8. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


9. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


10. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


11. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


12. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


13. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


14. The compound of claim 1, wherein the compound is


15. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


16. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


17. The compound of claim 1, wherein the compound is


18. The compound of claim 1, wherein the compound is


19. The compound of claim 1, wherein the compound is


20. The compound of claim 1, wherein the compound is


21. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


22. The compound of claim 1, wherein the compound is


23. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


24. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


25. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


26. The compound of claim 1, wherein the compound is


27. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


28. The compound of claim 1, wherein the compound is


29. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


30. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


31. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


32. The compound of claim 1, wherein the compound is


33. The compound of claim 1, wherein the compound is


34. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


35. The compound of claim 1, wherein the compound is


36. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


37. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


38. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


39. The compound of claim 1, wherein the compound is


40. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


41. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


42. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


43. The compound of claim 1, wherein the compound is


44. The compound of claim 1, wherein the compound is


45. The compound of claim 1, wherein the compound is


46. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


47. The compound of claim 1, wherein the compound is


48. The compound of claim 1, wherein the compound is


49. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


50. The compound of claim 1, wherein the compound is


51. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


52. The compound of claim 1, wherein the compound is


53. The compound of claim 1, wherein the compound is


54. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


55. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


56. The compound of claim 1, wherein the compound is


57. The compound of claim 1, wherein the compound is


58. The compound of claim 1, wherein the compound is


59. The compound of claim 1, wherein the compound is


60. The compound of claim 1, wherein the compound is


61. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


62. The compound of claim 1, wherein the compound is


63. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


64. The compound of claim 1, wherein the compound is


65. The compound of claim 1, wherein the compound is


66. The compound of claim 1, wherein the compound is


67. The compound of claim 1, wherein the compound is selected from thegroup consisting of:


68. The compound of claim 1, wherein the compound is


69. The compound of claim 1, wherein the compound is


70. The compound of claim 1, wherein the compound is


71. The compound of claim 1, wherein the compound is


72. The compound of claim 1, wherein the compound is


73. The compound of claim 1, wherein the compound is


74. The compound of claim 1, wherein the compound is


75. A method for treating an angiogenic-associated disorder, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of at least one compound of any one of claim 1, orpharmaceutically acceptable salts, hydrates, solvates, crystal forms,N-oxide(s), and individual diastereomers thereof, to a subject in needof such treatment.
 76. The method of claim 75, wherein the disorder is amyeloproliferative disorder, polycythemia vera, essentialthrombocythemia, myeloid fibrosis with myeloid metaplasia, any othermyeloid-linked disorder, proliferative diabetic retinopathy, a cancer,eye disease, inflammation, psoriasis, any disease related toangiogenesis, or a viral infection.
 77. The method of claim 75, whereinthe disorder is polycythemia vera.
 78. The method of claim 75, whereinthe disorder is essential thrombocythemia.
 79. The method of claim 75,wherein the disorder is myeloid fibrosis with myeloid metaplasia. 80.The method of claim 75, wherein the disorder is any myeloid-linkeddisorder.
 81. The method of claim 76, wherein the cancer is selectedfrom a group consisting of an alimentary/gastrointestinal tract cancer,colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer,prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, musclecancer, bone cancer, bladder cancer and brain cancer.
 82. The method ofclaim 75, wherein the disorder is selected from a group consisting ofocular neovasculariaztion, infantile haemangiomas; organ hypoxia,vascular hyperplasia, organ transplant rejection, lupus, multiplesclerosis, rheumatoid arthritis, psoriasis, Type I diabetes, or Type IIdiabetes, and complications from diabetes, inflammatory disease, acutepancreatitis, chronic pancreatitis, asthma, allergies, adult respiratorydistress syndrome, cardiovascular disease, liver disease, other blooddisorders, asthma, rhinitis, atopic, dermatitits, autoimmune thryroiddisorders, ulerative colitis, Crohn's disease, metastatic melanoma,Kaposi's sarcoma, multiple myeloma, conditions associated withcytokines, and other autoimmune diseases including glomerulonephritis,scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis,autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia,allergic asthma, atopic dermatitis, allergic rhinitis, chronic activehepatitis, myasthenia gravis, multiple sclerosis, inflammatory boweldisease, graft vs host disease, motor neuron disease, Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's disease, cerebral ischemia, or neurodegenerative diseasecaused by traumatic injury, strike, gluatamate neurtoxicity, hypoxia;ischemic/reperfusion injury in stroke, myocardial ischemica, renalischemia, heart attacks, cardiac hypertrophy, atherosclerosis andarteriosclerosis, organ hyoxia, platelet aggregation, allergic contactdermatitis, hypersensitivity pneumonitis, systemic lupus erythematosus,juvenile arthritis, Sjogren's Syndrome, scleroderma, polymyositis,ankylosing spondylitis, psoriatic arthritis, Epstein Barr Virus,Hepatitis B, Hepatitis C, HIV, HTLV1, Vaicella-Zoster Virus, HumanPapilloma Virus, food allergy, cutaneous inflammation, and immunesuppression induced by solid tumors.
 83. The method of claim 82, whereinthe disorder is cardiovascular disease.
 84. The method of claim 82,wherein the disorder is a hematological disorder.
 85. The method ofclaim 75, wherein the disorder is chronic myelogenous leukemia (CML).86. The method of claim 85, wherein said chronic myelogenous leukemia isresistant to current treatments.
 87. The method of claim 75, wherein thedisorder is a myeloproliferative disorder.
 88. The method of claim 87,wherein the myeloproliferative disorder arises due to mutations in akinase.
 89. The method of claim 88, wherein the kinase is a JAK familykinase.
 90. The method of claim 87, wherein the myeloproliferativedisorder arises due to gain-of-function of a JAK family kinase pathway.91. The method of claim 87, wherein the myeloproliferative disorderarises as a result of gene or protein fusions due to gain-of-function ofa JAK family kinase pathway.
 92. The method of claim 75, wherein thedisorder is associated with a kinase.
 93. The method of claim 92,wherein the kinase is a JAK family kinase.
 94. A pharmaceuticalcomposition comprising at least one compound of any one of claims 1-3,or its N-oxides, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual diastereomers thereof, and apharmaceutically acceptable carrier therefore.
 95. An article ofmanufacture comprising packaging material and a pharmaceuticalcomposition contained within the packaging material, wherein thepackaging material comprises a label which indicates that thepharmaceutical composition can be used for treatment ofangiogenic-associated disorders, and wherein the pharmaceuticalcomposition comprises at least one compound of any one of claims 1-3, orN-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates,crystal forms and individual diastereomers thereof.
 96. An article ofmanufacture comprising packaging material and a pharmaceuticalcomposition contained within the packaging material, wherein thepackaging material comprises a label which indicates that thepharmaceutical composition can be used for treatment ofmyeloproliferative disorder, proliferative diabetic retinopathy, acancer, eye disease, inflammation, psoriasis, or a viral infection, andwherein the pharmaceutical composition comprises at least one compoundof any one of claim 1, or N-oxides, or pharmaceutically acceptablesalts, hydrates, solvates, crystal forms and individual diastereomersthereof.
 97. The article of manufacture of claim 96, wherein thedisorder is selected from a group consisting of analimentary/gastrointestinal tract cancer, colon cancer, liver cancer,skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma,leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer,bladder cancer and brain cancer.
 98. A method of treatingangiogenic-associated disorder, comprising the administration of atherapeutically effective amount of at least one compound of any one ofclaims 1-3, or N-oxide(s), or pharmaceutically acceptable salts,hydrates, solvates, crystal forms and individual diastereomers thereof,in combination with an anti-inflammatory agent, chemotherapeutic agent,immunomodulatory agent, therapeutic antibody, or a protein kinaseinhibitor, to a subject in need of such treatment.
 99. A process formaking a pharmaceutical composition comprising combining a combinationof at least one compound of any one of claims 1-3, or its N-oxide(s), orits pharmaceutically acceptable salts, hydrates, solvates, crystal formssalts and individual diastereomers thereof, and a pharmaceuticallyacceptable carrier.
 100. A method of treating angiogenic-associateddisorder, comprising the topical administration of a therapeuticallyeffective amount of at least one compound of any one of claim 1, orN-oxide(s), or pharmaceutically acceptable salts, hydrates, solvates,crystal forms and individual diastereomers thereof, to a subject in needof such treatment.
 101. The method of claim 100, wherein theadministration is carried out in combination with administering ananti-inflammatory agent, chemotherapeutic agent, immunomodulatory agent,therapeutic antibody, or a protein kinase inhibitor.
 102. The method ofclaim 100 or 101, wherein the disorder is an eye disease.
 103. Themethod of claim 102, wherein the topical administration comprisesadministering eye drops.
 104. A compound having the structure (B):

wherein: X is selected from a group consisting of a bond, O, C═O, SO₂,and CH₂; Y is selected from a group consisting of a bond or NR⁹; or Xand Y taken together is a bond; R⁹ is selected from a group consistingof H, C₁-C₆ alkyl, C₁-C₆ cycloalkyl, C₁-C₆ branched alkyl, C₁-C₆substituted alkyl, C₁-C₆ aminoalkyl, and C₁-C₆ hydroxyalkyl; each of R¹is independently selected from a group consisting of H, C₁-C₆substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycle, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl; each ofn, or p is independently an integer having the value between 0 and 6; Q₁is a 4-7 membered heterocycle connected through carbon or nitrogen, withone or more heteroatoms in the heterocyle, and each carbon or nitrogenin the heterocycle is optionally substituted independently with C₁-C₆substituted or unsubstituted alkyl, C₁-C₆ substituted or unsubstitutedalkenyl, C₁-C₆ substituted or unsubstituted alkynyl, C₁-C₆ substitutedor unsubstituted hydroxyalkyl or aminoalkyl, C₁-C₆ substituted orunsubstituted branched alkyl, C₁-C₆ substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl connected through carbonor a heteroatom, substituted or unsubstituted heteroaryl connectedthrough carbon or a heteroatom, a halogen, CF₃, —OCF₃, NO₂, CN, OH,CONR³R⁴, and COR³; each of R⁶, R⁷, R⁸ is independently selected from agroup consisting of H, C₁-C₆ substituted or unsubstituted alkyl, C₁-C₆substituted or unsubstituted alkenyl, C₁-C₆ substituted or unsubstitutedalkynyl, C₁-C₆ substituted or unsubstituted hydroxyalkyl or aminoalkyl,C₁-C₆ substituted or unsubstituted branched alkyl, C₁-C₆ substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl connectedthrough carbon or a heteroatom, substituted or unsubstituted heteroarylconnected through carbon or a heteroatom, C₁-C₆ alkoxy, a halogen, CF₃,—OCF₃, CHR³R⁴, SR³, SOR³, SO₂R³, SO₂NR³R⁴, SO₃R³, POR³, PO₂R³, PO₂NR³R⁴,PO₂CR³R⁴, PO₃R³, NR³R⁴, NO₂, CN, OH, CONR³R⁴, COR³, COOR³, NR³COR⁴,NR³CONR³R⁴, OCONR³R⁴, CSNR³R⁴, CSR³, NR³CSNR³R⁴, SCONR³R⁴, SCSNR³R⁴, andSCSNR³R⁴; or any of R⁶ and R⁷ taken together, or R⁷ and R⁸ takentogether, or R⁶ and R⁸ taken together form a moiety independentlyselected from a group consisting of —HN—CH═CH—, —HN—N═CH—, —HN—N═N—,—O(CH₂)_(n)O—, —S(CH₂)_(n)S—, —N═CH—S—, —CH═N—O—, —CH═N—S—, —N═CH—O—,—C═N—O—, —C═N—O—, —CH═CH—CH═CH—, —N═CH—CH═CH—, —CH═N—CH═CH—, —O—CH═CH,and —S—CH═CH—; each of R³ and R⁴ is independently selected from a groupconsisting of H, C₁-C₆ alkyl, C₁-C₆ substituted or unsubstitutedhydroxyalkyl or aminoalkyl, C₁-C₆ substituted or unsubstituted branchedalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl with the further provisos that: (a) at leastone of R⁶, R⁷ and R⁸ is not hydrogen; (b) R⁶ and R⁷, or R⁶ and R⁸, or R⁷and R⁸ are substituted with non-hydrogen atoms, or if only one of R⁶, R⁷and R⁸ is substituted, then the substitution contains at least threenon-hydrogen atoms; (c) any one of R⁶, R⁷ or R⁸ optionally comprises aheteroatom selected from a group consisting of O, N and S; (d) themoiety connected through X excludes aromatic or hetero-aromatic cyclicrings, or pharmaceutically acceptable salts, hydrates, solvates, crystalforms, N-oxides, and individual diastereomers of the compound (B). 105.The compound of claim 104, having the structure (C):


106. The compound of claim 104, having the structure (D):

wherein the moiety attached to a connection point shown in structure (D)is selected from a group consisting of:


107. The compound of claim 104, having the structure (E):


108. The compound of claim 104, having the structure (F):

wherein the moiety attached to a connection point shown in structure (F)is selected from a group consisting of:


109. The compound of claim 104, having the structure (G):


110. The compound of claim 104, having the structure (H):

wherein the moiety attached to a connection point shown in structure (H)is selected from a group consisting of:


111. The compound of claim 104, having the structure (I):

wherein the moiety attached to a connection point shown in structure (H)is selected from a group consisting of:


112. The compound of claim 104, having the structure (J):

wherein the moiety attached to a connection point shown in structure (J)is